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What was the administration route of drug 'DOXORUBICIN'? | Survival of large volume recurrent endometrial cancer with peritoneal metastases treated by cytoreductive surgery, HIPEC and EPIC. Report of a case.
Endometrial cancer may disseminate through lymphatic channels to pelvic and retroperitoneal lymph nodes, through the bloodstream to the lungs, or through the peritoneal space to peritoneal surfaces. However, not all endometrial cancers involve all 3 sites for metastatic disease.
METHODS
A patient with large volume of symptomatic recurrence of peritoneal metastases from endometrial cancer was subjected to additional surgery and both regional and systemic chemotherapy. All aspects of her disease and its treatment were studied.
The primary malignancy was treated by a laparoscopic hysterectomy and bilateral salpingo-oophorectomy followed by intravaginal radiation. Large volume recurrent disease limited to the abdomen and pelvis was treated by complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC). After recovery from surgery, systemic chemotherapy with cisplatin and paclitaxel was administered. The patient is now 25 months following treatment for recurrent cancer and free of disease.
CONCLUSIONS
The possibility of complete resection of recurrent endometrial cancer combined with HIPEC, EPIC and systemic chemotherapy is a treatment option for selected patients.
1 Introduction
Endometrial cancer is confined to the corpus uteri at the time of diagnosis in a large majority of patients [1,2]. Also, most of these patients are cured of disease by hysterectomy with or without pelvic and para-aortic lymph node dissection. Radiation therapy, usually recommended in the past, is less frequently or not used at all [3]. Combination chemotherapy is increasingly used by systemic administration. A regional (intraperitoneal chemotherapy) treatment has seldom been used in the past. This lack of enthusiasm for a regional route of administration may be questioned in that the most common sites of disease dissemination in patients thought to have uterine-confine disease is the peritoneal space. Positive peritoneal cytology was documented in 12%, 5% had adnexal involvement and 6% had gross intraperitoneal metastases [4]. These patients with early peritoneal disease at the time of primary resection will most commonly fail treatment within the peritoneal cavity [5]. Therapies may be individualized by determining the most likely sites for metastatic disease documented by careful follow-up [6].
Although not mentioned in the standard textbooks, surgery for recurrent endometrial cancer has been reported with some success. Papadia and coworkers reported a 5-year disease-free survival of 42% in 42 patients with optimal cytoreduction [7]. Cornali and coworkers added HIPEC with cisplatin to a cytoreductive surgery for 33 patients with peritoneal metastases from recurrent endometrial cancer. The 5-year overall survival was 30% (median survival was 33.1 months) [8]. The completeness of cytoreduction was the only significant factor independently influencing overall survival (p = 0.016). Goere et al. reported on 20 patients who underwent CRS and HIPEC for recurrent endometrial cancer [9].
In this case report, a patient with extensive recurrent endometrial cancer confined to the abdomen and pelvis was treated with a complete CRS, multiagent HIPEC and EPIC paclitaxel. She remains disease-free at 25 months after her intervention for recurrent disease. The ramifications of this outcome for patients who have a high propensity for progression of peritoneal metastases is discussed.
2 Patient presentation
Data on this patient was prospectively recorded and then retrospectively reviewed at an academic institution. This research work has been reported in line with the SCARE 2020 criteria [10]. This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
September 2016: At age 57, this woman developed postmenopausal bleeding. A Pap smear revealed malignant cells.
January 2017: A laparoscopic total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed by a gynecologic oncologist. Right and left sentinel pelvic lymph nodes were negative as were biopsies from right and left para-aortic lymph nodes. The endometrioid adenocarcinoma of the endometrium was FIGO grade 2 of 3. The tumor size was 3.5 cm in diameter. The histologic type was endometrioid adenocarcinoma with focal squamous differentiation. The patient underwent 5 cycles of intravaginal chemotherapy.
September 2018: The patient had an episode of urinary retention with severe discomfort upon urination. A CT scan showed disease within the greater omentum (Fig. 1), a mass associated with the transverse colon (Fig. 2) and a nodule between right and left common iliac vessels thought to be a para-aortic lymph node (Fig. 3).Fig. 1 CT scan through the upper abdomen shows cancer infiltration of the greater omentum.
Fig. 1
Fig. 2 At the level of the umbilicus, CT shows an 8 cm mass associated with the mid-transverse colon. No bowel obstruction is evident.
Fig. 2
Fig. 3 A nodule interpreted as a lymph node at the bifurcation of the aorta is seen between the right and left common iliac vessels.
Fig. 3
An encounter summary performed in the Cancer Institute recorded no drug history, no family history of cancer, and a totally normal psychosocial history.
Physical examination showed a prominent mass in the left upper quadrant which extended transversely along the abdominal wall. On pelvic exam, there were masses on the left side of the pelvis and at the apex of the vagina.
The results of the evaluation for recurrent endometrial cancer including the masses by physical examination and the marked progression of disease by CT were discussed with the patient. The possible options for treatment were discussed at a combined surgical oncology/gynecologic oncology multidisciplinary team (MDT) meeting. Given the patient’s young age and lack of comorbid conditions, a reoperative surgery plus HIPEC was recommended. This information was again, at a separate visit, communicated to the patient and her family. The possibility for adverse events and their incidence were discussed. The patient elected to move toward the cytoreductive surgery which was scheduled within 10 days. The patient was treated as part of an ongoing performance improvement project with extensive data monitoring.
October 2018: An 11-h cytoreductive surgery was performed with HIPEC by a surgical oncologist (PHS). Procedures performed included greater omentectomy, splenectomy, cholecystectomy, lesser omentectomy, peritonectomy of the undersurface of the right hemidiaphragm, partial peritonectomy of the left hemidiaphragm, transverse colectomy with anastomosis, pelvic peritonectomy and bilateral ureterolysis. The apex of the vagina was resected for approximately 4 cm because of disease at that site [11]. All specimens except the gallbladder were positive for metastatic high-grade carcinoma. The nodule at the bifurcation of the aorta was removed and submitted as a separate specimen. It was a nodule of high-grade carcinoma but was not thought to be within a lymph node. Fig. 4 shows the peritoneal cancer index.Fig. 4 The peritoneal cancer index (PCI). The PCI combines size and distribution parameters to determine a numerical score. The lesion size (LS) is used to quantitate the size of the peritoneal nodules with the 13 abdomino-pelvic regions. LS-0 indicates no tumor seen, LS-1 indicates tumor implants up to 0.5 cm, LS-2 indicates tumor implants between 0.5 and 5 cm, and LS-3 indicates tumor implants larger than 5 cm or a layering of cancer. The PCI in a 59-year-old woman undergoing surgery for recurrent endometrial high-grade carcinoma is shown in the diagram. The PCI was 20.
Fig. 4
The patient received hyperthermic intraperitoneal chemotherapy for 90 min with cisplatin 80 mg, doxorubicin 24 mg, and intravenous ifosfamide 2080 mg. Mesna was given prior to ifosfamide infusion, 4 h after completion of chemotherapy and 8 h after completion of chemotherapy at 416 mg. Temperature within the peritoneal space was approximately 42.5–43.5 °C [12].
Postoperatively, the patient received EPIC paclitaxel at 32 mg/day in 1 L of hetastarch solution for 5 consecutive days. The total dose of paclitaxel was 160 mg [12]. The patient developed a wound infection which was treated with antibiotics and opening of the lower 3 cm of the abdominal incision. The patient was discharged on her 21st postoperative day. There were no class 3 or 4 adverse events. The HIPEC and EPIC were well tolerated.
The patient received 5 cycles of systemic chemotherapy using cisplatin and paclitaxel delivered by a medical oncologist. A planned sixth cycle of systemic chemotherapy was withheld because of cumulative cisplatin toxicity.
Postoperatively, CT have been performed on a 6 monthly basis.
At 25 months postoperatively, a CT scan of the chest, abdomen and pelvis showed no progression of disease. CA-125 tumor marker was negative prior to surgery and has not shown elevation. The patient is maintained on oral nutrition without supplements and is maintaining here preoperative weight. No pain medicines are required.
3 Discussion
3.1 Treatment and prevention of peritoneal spread is possible
This case report illustrates that peritoneal metastases from endometrial cancer, even of large volume, can be controlled with a combination of complete resection and combined regional and systemic chemotherapy. Other reports attempt to convey the same message [8,9]. It is important to realize that the timing of the two components of this treatment strategy are crucial to its success. The surgery must remove all visible evidence of disease using a combination of peritonectomy procedures and visceral resections [11]. Then before stray cancer cells have the opportunity to become fixed within a fibrinous matrix, they must be washed by a chemotherapy solution to remove them mechanically and initiate chemotherapy-induced apoptosis. The current treatment option to supplement complete cytoreduction is HIPEC or HIPEC plus EPIC as was used in this patient [12]. Success in the management of peritoneal metastases from endometrial cancer is possible.
3.2 Careful study of the primary cancer may reveal the natural history of treatment failure
As published by Creasman and coworkers in a Gynecologic Oncology Group study, positive peritoneal cytology and/or peritoneal metastases are present in approximately 20% of primary endometrial cancers. The extent of the peritoneal spread and its documentation is not available from the pathologist for approximately one week following the surgical procedure. Morrow and coworkers have suggested that there is a relationship between the surgical-pathologic risk factors and the patient’s outcome [13]. Also, Mariani and coworkers more specifically showed that the findings within the resected endometrial cancer specimen can predict later progression of peritoneal metastases [5]. If CRS and HIPEC were utilized to eliminate peritoneal dissemination in patients at high risk for this type of treatment failure, an improved outcome is expected.
3.3 A new and expanded role for the pathologist in patients with endometrial cancer
Currently, a large amount of crucial information regarding the outcome of cancer patients is provided by the pathologist. The resected specimen is placed in formalin to be prosected by the pathologist at a later and convenient time. For interventions that occur at the time of cancer resection, such as CRS and HIPEC, this information is “after the fact.” Of course, very interesting, but not of benefit to the patient who may be in need of preventative treatment for subsequent progression of peritoneal disease. For peritonectomy procedures to be used to resect peritoneal metastases at a particular site, the anatomic site of disease must be documented histopathologically in the operating theater. Return to perform a second-look at a later time is not a realistic plan. Also, results of peritoneal cytology are needed while the patient is in the operating room to make a decision regarding HIPEC or HIPEC with EPIC.
3.4 Intraoperative surgical-pathological collaboration
In order to make the prediction of high risk for peritoneal recurrence/progression relevant to an individual patient, information must be made available in the operating theater. Immediately after the specimen is removed, it must be oriented by the surgeon for the pathologist. All peritoneal or Fallopian tube biopsies suspicious for peritoneal metastases must be presented to the pathologist. The peritoneal cytology results must be determined. The uterus specimen must be examined for peritoneal infiltration. Together the surgeon and pathologist need to make a decision regarding the subsequent risk of the individual patient for peritoneal metastases. If there is a risk, peritonectomy of selected anatomic sites may be required. Also, HIPEC or HIPEC plus EPIC administration requires an intraoperative judgment to proceed. In addition, prior consent for these interventions are required. By cryostat sections, the histopathological information needs to be available in the operating theater to administer the individualized treatments that are indicated in a timely manner.
3.5 CRS and HIPEC failures despite treatment
In the patient in this case report, the small bowel and its mesentery were observed to be free of peritoneal metastases. This is a favorable observation that indicates long-term success may be possible even with large masses of tumor distributed on the parietal peritoneum. Cytoreduction of small bowel and its mesentery is especially difficult. Extensive resection of small bowel is to be avoided. Also, tumor nodule removal on the bowel surface places the patient at risk for postoperative fistula. Removal of tumor from the mesentery creates a risk for small bowel ischemia. This is a major concern if tumor nodules are at the junction of small bowel with its mesentery. The mechanism for persistence and then subsequent progression of peritoneal metastases on visceral peritoneum has not been elucidated. However, incomplete resection combined with rapid removal of cancer chemotherapy with a generous blood supply within the small bowel may combine to cause the poor result. Small bowel sparing is important to the long-term success of CRS and HIPEC.
3.6 Bidirectional chemotherapy with HIPEC and EPIC for prevention or treatment of resected endometrial cancer with peritoneal metastases
For the chemotherapy agents used in this patient with peritoneal metastases from endometrial cancer, drugs with known response for this disease were selected. For HIPEC, the intraperitoneal drugs were moderate dose cisplatin and doxorubicin. Both of these drugs have activity for endometrial cancer and both are augmented in their cytotoxicity by heat. Both drugs have a favorable area under the curve ratio of intraperitoneal to systemic drug concentration. They are both acute phase agents and produce their full cytotoxic effect within the 90-minute HIPEC treatment [14]. A single systemic agent is ifosfamide. Our pharmacologic studies show that the same concentrations of intravenous and intraperitoneal ifosfamide are present almost immediately after intravenous infusion [15]. The intravenous ifosfamide has been shown to gain access to peritoneal tumor nodules.
For EPIC, paclitaxel was selected. This drug has a prolonged dwell time within the peritoneal space because of its large molecular weight. Also, it is a non-vesicant drug and well tolerated by the peritoneum without causing fibrosis [16]. Markman and coworkers demonstrated a 61% complete response rate in 28 patients with microscopic residual disease [17].
Declaration of Competing Interest
Paul H. Sugarbaker has no conflicts of interest to declare.
Funding
Data management and secretarial support provided by Foundation for Applied Research in Gastrointestinal Oncology.
Ethical approval
MedStar Health Institutional Review Board has determined that a case report of less than three (3) patients does not meet the DHHS definition of research (45 CFR 46.102(d)(pre-2018)/45 CFR46.102(l)(1/19/2017)) or the FDA definition of clinical investigation (21 CFR 46.102(c)) and therefore are not subject to IRB review requirements and do not require IRB approval.
Consent
Written and signed consent was obtained from the patient.
Author contribution
Paul H. Sugarbaker: study concept or design, data collection, data analysis or interpretation, writing the paper.
Registration of research studies
This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
Guarantor
Paul H. Sugarbaker, MD
Provenance and peer review
Not commissioned, externally peer-reviewed. | Intraperitoneal | DrugAdministrationRoute | CC BY-NC-ND | 33667906 | 19,025,392 | 2021-03 |
What was the administration route of drug 'IFOSFAMIDE'? | Survival of large volume recurrent endometrial cancer with peritoneal metastases treated by cytoreductive surgery, HIPEC and EPIC. Report of a case.
Endometrial cancer may disseminate through lymphatic channels to pelvic and retroperitoneal lymph nodes, through the bloodstream to the lungs, or through the peritoneal space to peritoneal surfaces. However, not all endometrial cancers involve all 3 sites for metastatic disease.
METHODS
A patient with large volume of symptomatic recurrence of peritoneal metastases from endometrial cancer was subjected to additional surgery and both regional and systemic chemotherapy. All aspects of her disease and its treatment were studied.
The primary malignancy was treated by a laparoscopic hysterectomy and bilateral salpingo-oophorectomy followed by intravaginal radiation. Large volume recurrent disease limited to the abdomen and pelvis was treated by complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC). After recovery from surgery, systemic chemotherapy with cisplatin and paclitaxel was administered. The patient is now 25 months following treatment for recurrent cancer and free of disease.
CONCLUSIONS
The possibility of complete resection of recurrent endometrial cancer combined with HIPEC, EPIC and systemic chemotherapy is a treatment option for selected patients.
1 Introduction
Endometrial cancer is confined to the corpus uteri at the time of diagnosis in a large majority of patients [1,2]. Also, most of these patients are cured of disease by hysterectomy with or without pelvic and para-aortic lymph node dissection. Radiation therapy, usually recommended in the past, is less frequently or not used at all [3]. Combination chemotherapy is increasingly used by systemic administration. A regional (intraperitoneal chemotherapy) treatment has seldom been used in the past. This lack of enthusiasm for a regional route of administration may be questioned in that the most common sites of disease dissemination in patients thought to have uterine-confine disease is the peritoneal space. Positive peritoneal cytology was documented in 12%, 5% had adnexal involvement and 6% had gross intraperitoneal metastases [4]. These patients with early peritoneal disease at the time of primary resection will most commonly fail treatment within the peritoneal cavity [5]. Therapies may be individualized by determining the most likely sites for metastatic disease documented by careful follow-up [6].
Although not mentioned in the standard textbooks, surgery for recurrent endometrial cancer has been reported with some success. Papadia and coworkers reported a 5-year disease-free survival of 42% in 42 patients with optimal cytoreduction [7]. Cornali and coworkers added HIPEC with cisplatin to a cytoreductive surgery for 33 patients with peritoneal metastases from recurrent endometrial cancer. The 5-year overall survival was 30% (median survival was 33.1 months) [8]. The completeness of cytoreduction was the only significant factor independently influencing overall survival (p = 0.016). Goere et al. reported on 20 patients who underwent CRS and HIPEC for recurrent endometrial cancer [9].
In this case report, a patient with extensive recurrent endometrial cancer confined to the abdomen and pelvis was treated with a complete CRS, multiagent HIPEC and EPIC paclitaxel. She remains disease-free at 25 months after her intervention for recurrent disease. The ramifications of this outcome for patients who have a high propensity for progression of peritoneal metastases is discussed.
2 Patient presentation
Data on this patient was prospectively recorded and then retrospectively reviewed at an academic institution. This research work has been reported in line with the SCARE 2020 criteria [10]. This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
September 2016: At age 57, this woman developed postmenopausal bleeding. A Pap smear revealed malignant cells.
January 2017: A laparoscopic total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed by a gynecologic oncologist. Right and left sentinel pelvic lymph nodes were negative as were biopsies from right and left para-aortic lymph nodes. The endometrioid adenocarcinoma of the endometrium was FIGO grade 2 of 3. The tumor size was 3.5 cm in diameter. The histologic type was endometrioid adenocarcinoma with focal squamous differentiation. The patient underwent 5 cycles of intravaginal chemotherapy.
September 2018: The patient had an episode of urinary retention with severe discomfort upon urination. A CT scan showed disease within the greater omentum (Fig. 1), a mass associated with the transverse colon (Fig. 2) and a nodule between right and left common iliac vessels thought to be a para-aortic lymph node (Fig. 3).Fig. 1 CT scan through the upper abdomen shows cancer infiltration of the greater omentum.
Fig. 1
Fig. 2 At the level of the umbilicus, CT shows an 8 cm mass associated with the mid-transverse colon. No bowel obstruction is evident.
Fig. 2
Fig. 3 A nodule interpreted as a lymph node at the bifurcation of the aorta is seen between the right and left common iliac vessels.
Fig. 3
An encounter summary performed in the Cancer Institute recorded no drug history, no family history of cancer, and a totally normal psychosocial history.
Physical examination showed a prominent mass in the left upper quadrant which extended transversely along the abdominal wall. On pelvic exam, there were masses on the left side of the pelvis and at the apex of the vagina.
The results of the evaluation for recurrent endometrial cancer including the masses by physical examination and the marked progression of disease by CT were discussed with the patient. The possible options for treatment were discussed at a combined surgical oncology/gynecologic oncology multidisciplinary team (MDT) meeting. Given the patient’s young age and lack of comorbid conditions, a reoperative surgery plus HIPEC was recommended. This information was again, at a separate visit, communicated to the patient and her family. The possibility for adverse events and their incidence were discussed. The patient elected to move toward the cytoreductive surgery which was scheduled within 10 days. The patient was treated as part of an ongoing performance improvement project with extensive data monitoring.
October 2018: An 11-h cytoreductive surgery was performed with HIPEC by a surgical oncologist (PHS). Procedures performed included greater omentectomy, splenectomy, cholecystectomy, lesser omentectomy, peritonectomy of the undersurface of the right hemidiaphragm, partial peritonectomy of the left hemidiaphragm, transverse colectomy with anastomosis, pelvic peritonectomy and bilateral ureterolysis. The apex of the vagina was resected for approximately 4 cm because of disease at that site [11]. All specimens except the gallbladder were positive for metastatic high-grade carcinoma. The nodule at the bifurcation of the aorta was removed and submitted as a separate specimen. It was a nodule of high-grade carcinoma but was not thought to be within a lymph node. Fig. 4 shows the peritoneal cancer index.Fig. 4 The peritoneal cancer index (PCI). The PCI combines size and distribution parameters to determine a numerical score. The lesion size (LS) is used to quantitate the size of the peritoneal nodules with the 13 abdomino-pelvic regions. LS-0 indicates no tumor seen, LS-1 indicates tumor implants up to 0.5 cm, LS-2 indicates tumor implants between 0.5 and 5 cm, and LS-3 indicates tumor implants larger than 5 cm or a layering of cancer. The PCI in a 59-year-old woman undergoing surgery for recurrent endometrial high-grade carcinoma is shown in the diagram. The PCI was 20.
Fig. 4
The patient received hyperthermic intraperitoneal chemotherapy for 90 min with cisplatin 80 mg, doxorubicin 24 mg, and intravenous ifosfamide 2080 mg. Mesna was given prior to ifosfamide infusion, 4 h after completion of chemotherapy and 8 h after completion of chemotherapy at 416 mg. Temperature within the peritoneal space was approximately 42.5–43.5 °C [12].
Postoperatively, the patient received EPIC paclitaxel at 32 mg/day in 1 L of hetastarch solution for 5 consecutive days. The total dose of paclitaxel was 160 mg [12]. The patient developed a wound infection which was treated with antibiotics and opening of the lower 3 cm of the abdominal incision. The patient was discharged on her 21st postoperative day. There were no class 3 or 4 adverse events. The HIPEC and EPIC were well tolerated.
The patient received 5 cycles of systemic chemotherapy using cisplatin and paclitaxel delivered by a medical oncologist. A planned sixth cycle of systemic chemotherapy was withheld because of cumulative cisplatin toxicity.
Postoperatively, CT have been performed on a 6 monthly basis.
At 25 months postoperatively, a CT scan of the chest, abdomen and pelvis showed no progression of disease. CA-125 tumor marker was negative prior to surgery and has not shown elevation. The patient is maintained on oral nutrition without supplements and is maintaining here preoperative weight. No pain medicines are required.
3 Discussion
3.1 Treatment and prevention of peritoneal spread is possible
This case report illustrates that peritoneal metastases from endometrial cancer, even of large volume, can be controlled with a combination of complete resection and combined regional and systemic chemotherapy. Other reports attempt to convey the same message [8,9]. It is important to realize that the timing of the two components of this treatment strategy are crucial to its success. The surgery must remove all visible evidence of disease using a combination of peritonectomy procedures and visceral resections [11]. Then before stray cancer cells have the opportunity to become fixed within a fibrinous matrix, they must be washed by a chemotherapy solution to remove them mechanically and initiate chemotherapy-induced apoptosis. The current treatment option to supplement complete cytoreduction is HIPEC or HIPEC plus EPIC as was used in this patient [12]. Success in the management of peritoneal metastases from endometrial cancer is possible.
3.2 Careful study of the primary cancer may reveal the natural history of treatment failure
As published by Creasman and coworkers in a Gynecologic Oncology Group study, positive peritoneal cytology and/or peritoneal metastases are present in approximately 20% of primary endometrial cancers. The extent of the peritoneal spread and its documentation is not available from the pathologist for approximately one week following the surgical procedure. Morrow and coworkers have suggested that there is a relationship between the surgical-pathologic risk factors and the patient’s outcome [13]. Also, Mariani and coworkers more specifically showed that the findings within the resected endometrial cancer specimen can predict later progression of peritoneal metastases [5]. If CRS and HIPEC were utilized to eliminate peritoneal dissemination in patients at high risk for this type of treatment failure, an improved outcome is expected.
3.3 A new and expanded role for the pathologist in patients with endometrial cancer
Currently, a large amount of crucial information regarding the outcome of cancer patients is provided by the pathologist. The resected specimen is placed in formalin to be prosected by the pathologist at a later and convenient time. For interventions that occur at the time of cancer resection, such as CRS and HIPEC, this information is “after the fact.” Of course, very interesting, but not of benefit to the patient who may be in need of preventative treatment for subsequent progression of peritoneal disease. For peritonectomy procedures to be used to resect peritoneal metastases at a particular site, the anatomic site of disease must be documented histopathologically in the operating theater. Return to perform a second-look at a later time is not a realistic plan. Also, results of peritoneal cytology are needed while the patient is in the operating room to make a decision regarding HIPEC or HIPEC with EPIC.
3.4 Intraoperative surgical-pathological collaboration
In order to make the prediction of high risk for peritoneal recurrence/progression relevant to an individual patient, information must be made available in the operating theater. Immediately after the specimen is removed, it must be oriented by the surgeon for the pathologist. All peritoneal or Fallopian tube biopsies suspicious for peritoneal metastases must be presented to the pathologist. The peritoneal cytology results must be determined. The uterus specimen must be examined for peritoneal infiltration. Together the surgeon and pathologist need to make a decision regarding the subsequent risk of the individual patient for peritoneal metastases. If there is a risk, peritonectomy of selected anatomic sites may be required. Also, HIPEC or HIPEC plus EPIC administration requires an intraoperative judgment to proceed. In addition, prior consent for these interventions are required. By cryostat sections, the histopathological information needs to be available in the operating theater to administer the individualized treatments that are indicated in a timely manner.
3.5 CRS and HIPEC failures despite treatment
In the patient in this case report, the small bowel and its mesentery were observed to be free of peritoneal metastases. This is a favorable observation that indicates long-term success may be possible even with large masses of tumor distributed on the parietal peritoneum. Cytoreduction of small bowel and its mesentery is especially difficult. Extensive resection of small bowel is to be avoided. Also, tumor nodule removal on the bowel surface places the patient at risk for postoperative fistula. Removal of tumor from the mesentery creates a risk for small bowel ischemia. This is a major concern if tumor nodules are at the junction of small bowel with its mesentery. The mechanism for persistence and then subsequent progression of peritoneal metastases on visceral peritoneum has not been elucidated. However, incomplete resection combined with rapid removal of cancer chemotherapy with a generous blood supply within the small bowel may combine to cause the poor result. Small bowel sparing is important to the long-term success of CRS and HIPEC.
3.6 Bidirectional chemotherapy with HIPEC and EPIC for prevention or treatment of resected endometrial cancer with peritoneal metastases
For the chemotherapy agents used in this patient with peritoneal metastases from endometrial cancer, drugs with known response for this disease were selected. For HIPEC, the intraperitoneal drugs were moderate dose cisplatin and doxorubicin. Both of these drugs have activity for endometrial cancer and both are augmented in their cytotoxicity by heat. Both drugs have a favorable area under the curve ratio of intraperitoneal to systemic drug concentration. They are both acute phase agents and produce their full cytotoxic effect within the 90-minute HIPEC treatment [14]. A single systemic agent is ifosfamide. Our pharmacologic studies show that the same concentrations of intravenous and intraperitoneal ifosfamide are present almost immediately after intravenous infusion [15]. The intravenous ifosfamide has been shown to gain access to peritoneal tumor nodules.
For EPIC, paclitaxel was selected. This drug has a prolonged dwell time within the peritoneal space because of its large molecular weight. Also, it is a non-vesicant drug and well tolerated by the peritoneum without causing fibrosis [16]. Markman and coworkers demonstrated a 61% complete response rate in 28 patients with microscopic residual disease [17].
Declaration of Competing Interest
Paul H. Sugarbaker has no conflicts of interest to declare.
Funding
Data management and secretarial support provided by Foundation for Applied Research in Gastrointestinal Oncology.
Ethical approval
MedStar Health Institutional Review Board has determined that a case report of less than three (3) patients does not meet the DHHS definition of research (45 CFR 46.102(d)(pre-2018)/45 CFR46.102(l)(1/19/2017)) or the FDA definition of clinical investigation (21 CFR 46.102(c)) and therefore are not subject to IRB review requirements and do not require IRB approval.
Consent
Written and signed consent was obtained from the patient.
Author contribution
Paul H. Sugarbaker: study concept or design, data collection, data analysis or interpretation, writing the paper.
Registration of research studies
This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
Guarantor
Paul H. Sugarbaker, MD
Provenance and peer review
Not commissioned, externally peer-reviewed. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33667906 | 19,025,392 | 2021-03 |
What was the administration route of drug 'PACLITAXEL'? | Survival of large volume recurrent endometrial cancer with peritoneal metastases treated by cytoreductive surgery, HIPEC and EPIC. Report of a case.
Endometrial cancer may disseminate through lymphatic channels to pelvic and retroperitoneal lymph nodes, through the bloodstream to the lungs, or through the peritoneal space to peritoneal surfaces. However, not all endometrial cancers involve all 3 sites for metastatic disease.
METHODS
A patient with large volume of symptomatic recurrence of peritoneal metastases from endometrial cancer was subjected to additional surgery and both regional and systemic chemotherapy. All aspects of her disease and its treatment were studied.
The primary malignancy was treated by a laparoscopic hysterectomy and bilateral salpingo-oophorectomy followed by intravaginal radiation. Large volume recurrent disease limited to the abdomen and pelvis was treated by complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC). After recovery from surgery, systemic chemotherapy with cisplatin and paclitaxel was administered. The patient is now 25 months following treatment for recurrent cancer and free of disease.
CONCLUSIONS
The possibility of complete resection of recurrent endometrial cancer combined with HIPEC, EPIC and systemic chemotherapy is a treatment option for selected patients.
1 Introduction
Endometrial cancer is confined to the corpus uteri at the time of diagnosis in a large majority of patients [1,2]. Also, most of these patients are cured of disease by hysterectomy with or without pelvic and para-aortic lymph node dissection. Radiation therapy, usually recommended in the past, is less frequently or not used at all [3]. Combination chemotherapy is increasingly used by systemic administration. A regional (intraperitoneal chemotherapy) treatment has seldom been used in the past. This lack of enthusiasm for a regional route of administration may be questioned in that the most common sites of disease dissemination in patients thought to have uterine-confine disease is the peritoneal space. Positive peritoneal cytology was documented in 12%, 5% had adnexal involvement and 6% had gross intraperitoneal metastases [4]. These patients with early peritoneal disease at the time of primary resection will most commonly fail treatment within the peritoneal cavity [5]. Therapies may be individualized by determining the most likely sites for metastatic disease documented by careful follow-up [6].
Although not mentioned in the standard textbooks, surgery for recurrent endometrial cancer has been reported with some success. Papadia and coworkers reported a 5-year disease-free survival of 42% in 42 patients with optimal cytoreduction [7]. Cornali and coworkers added HIPEC with cisplatin to a cytoreductive surgery for 33 patients with peritoneal metastases from recurrent endometrial cancer. The 5-year overall survival was 30% (median survival was 33.1 months) [8]. The completeness of cytoreduction was the only significant factor independently influencing overall survival (p = 0.016). Goere et al. reported on 20 patients who underwent CRS and HIPEC for recurrent endometrial cancer [9].
In this case report, a patient with extensive recurrent endometrial cancer confined to the abdomen and pelvis was treated with a complete CRS, multiagent HIPEC and EPIC paclitaxel. She remains disease-free at 25 months after her intervention for recurrent disease. The ramifications of this outcome for patients who have a high propensity for progression of peritoneal metastases is discussed.
2 Patient presentation
Data on this patient was prospectively recorded and then retrospectively reviewed at an academic institution. This research work has been reported in line with the SCARE 2020 criteria [10]. This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
September 2016: At age 57, this woman developed postmenopausal bleeding. A Pap smear revealed malignant cells.
January 2017: A laparoscopic total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed by a gynecologic oncologist. Right and left sentinel pelvic lymph nodes were negative as were biopsies from right and left para-aortic lymph nodes. The endometrioid adenocarcinoma of the endometrium was FIGO grade 2 of 3. The tumor size was 3.5 cm in diameter. The histologic type was endometrioid adenocarcinoma with focal squamous differentiation. The patient underwent 5 cycles of intravaginal chemotherapy.
September 2018: The patient had an episode of urinary retention with severe discomfort upon urination. A CT scan showed disease within the greater omentum (Fig. 1), a mass associated with the transverse colon (Fig. 2) and a nodule between right and left common iliac vessels thought to be a para-aortic lymph node (Fig. 3).Fig. 1 CT scan through the upper abdomen shows cancer infiltration of the greater omentum.
Fig. 1
Fig. 2 At the level of the umbilicus, CT shows an 8 cm mass associated with the mid-transverse colon. No bowel obstruction is evident.
Fig. 2
Fig. 3 A nodule interpreted as a lymph node at the bifurcation of the aorta is seen between the right and left common iliac vessels.
Fig. 3
An encounter summary performed in the Cancer Institute recorded no drug history, no family history of cancer, and a totally normal psychosocial history.
Physical examination showed a prominent mass in the left upper quadrant which extended transversely along the abdominal wall. On pelvic exam, there were masses on the left side of the pelvis and at the apex of the vagina.
The results of the evaluation for recurrent endometrial cancer including the masses by physical examination and the marked progression of disease by CT were discussed with the patient. The possible options for treatment were discussed at a combined surgical oncology/gynecologic oncology multidisciplinary team (MDT) meeting. Given the patient’s young age and lack of comorbid conditions, a reoperative surgery plus HIPEC was recommended. This information was again, at a separate visit, communicated to the patient and her family. The possibility for adverse events and their incidence were discussed. The patient elected to move toward the cytoreductive surgery which was scheduled within 10 days. The patient was treated as part of an ongoing performance improvement project with extensive data monitoring.
October 2018: An 11-h cytoreductive surgery was performed with HIPEC by a surgical oncologist (PHS). Procedures performed included greater omentectomy, splenectomy, cholecystectomy, lesser omentectomy, peritonectomy of the undersurface of the right hemidiaphragm, partial peritonectomy of the left hemidiaphragm, transverse colectomy with anastomosis, pelvic peritonectomy and bilateral ureterolysis. The apex of the vagina was resected for approximately 4 cm because of disease at that site [11]. All specimens except the gallbladder were positive for metastatic high-grade carcinoma. The nodule at the bifurcation of the aorta was removed and submitted as a separate specimen. It was a nodule of high-grade carcinoma but was not thought to be within a lymph node. Fig. 4 shows the peritoneal cancer index.Fig. 4 The peritoneal cancer index (PCI). The PCI combines size and distribution parameters to determine a numerical score. The lesion size (LS) is used to quantitate the size of the peritoneal nodules with the 13 abdomino-pelvic regions. LS-0 indicates no tumor seen, LS-1 indicates tumor implants up to 0.5 cm, LS-2 indicates tumor implants between 0.5 and 5 cm, and LS-3 indicates tumor implants larger than 5 cm or a layering of cancer. The PCI in a 59-year-old woman undergoing surgery for recurrent endometrial high-grade carcinoma is shown in the diagram. The PCI was 20.
Fig. 4
The patient received hyperthermic intraperitoneal chemotherapy for 90 min with cisplatin 80 mg, doxorubicin 24 mg, and intravenous ifosfamide 2080 mg. Mesna was given prior to ifosfamide infusion, 4 h after completion of chemotherapy and 8 h after completion of chemotherapy at 416 mg. Temperature within the peritoneal space was approximately 42.5–43.5 °C [12].
Postoperatively, the patient received EPIC paclitaxel at 32 mg/day in 1 L of hetastarch solution for 5 consecutive days. The total dose of paclitaxel was 160 mg [12]. The patient developed a wound infection which was treated with antibiotics and opening of the lower 3 cm of the abdominal incision. The patient was discharged on her 21st postoperative day. There were no class 3 or 4 adverse events. The HIPEC and EPIC were well tolerated.
The patient received 5 cycles of systemic chemotherapy using cisplatin and paclitaxel delivered by a medical oncologist. A planned sixth cycle of systemic chemotherapy was withheld because of cumulative cisplatin toxicity.
Postoperatively, CT have been performed on a 6 monthly basis.
At 25 months postoperatively, a CT scan of the chest, abdomen and pelvis showed no progression of disease. CA-125 tumor marker was negative prior to surgery and has not shown elevation. The patient is maintained on oral nutrition without supplements and is maintaining here preoperative weight. No pain medicines are required.
3 Discussion
3.1 Treatment and prevention of peritoneal spread is possible
This case report illustrates that peritoneal metastases from endometrial cancer, even of large volume, can be controlled with a combination of complete resection and combined regional and systemic chemotherapy. Other reports attempt to convey the same message [8,9]. It is important to realize that the timing of the two components of this treatment strategy are crucial to its success. The surgery must remove all visible evidence of disease using a combination of peritonectomy procedures and visceral resections [11]. Then before stray cancer cells have the opportunity to become fixed within a fibrinous matrix, they must be washed by a chemotherapy solution to remove them mechanically and initiate chemotherapy-induced apoptosis. The current treatment option to supplement complete cytoreduction is HIPEC or HIPEC plus EPIC as was used in this patient [12]. Success in the management of peritoneal metastases from endometrial cancer is possible.
3.2 Careful study of the primary cancer may reveal the natural history of treatment failure
As published by Creasman and coworkers in a Gynecologic Oncology Group study, positive peritoneal cytology and/or peritoneal metastases are present in approximately 20% of primary endometrial cancers. The extent of the peritoneal spread and its documentation is not available from the pathologist for approximately one week following the surgical procedure. Morrow and coworkers have suggested that there is a relationship between the surgical-pathologic risk factors and the patient’s outcome [13]. Also, Mariani and coworkers more specifically showed that the findings within the resected endometrial cancer specimen can predict later progression of peritoneal metastases [5]. If CRS and HIPEC were utilized to eliminate peritoneal dissemination in patients at high risk for this type of treatment failure, an improved outcome is expected.
3.3 A new and expanded role for the pathologist in patients with endometrial cancer
Currently, a large amount of crucial information regarding the outcome of cancer patients is provided by the pathologist. The resected specimen is placed in formalin to be prosected by the pathologist at a later and convenient time. For interventions that occur at the time of cancer resection, such as CRS and HIPEC, this information is “after the fact.” Of course, very interesting, but not of benefit to the patient who may be in need of preventative treatment for subsequent progression of peritoneal disease. For peritonectomy procedures to be used to resect peritoneal metastases at a particular site, the anatomic site of disease must be documented histopathologically in the operating theater. Return to perform a second-look at a later time is not a realistic plan. Also, results of peritoneal cytology are needed while the patient is in the operating room to make a decision regarding HIPEC or HIPEC with EPIC.
3.4 Intraoperative surgical-pathological collaboration
In order to make the prediction of high risk for peritoneal recurrence/progression relevant to an individual patient, information must be made available in the operating theater. Immediately after the specimen is removed, it must be oriented by the surgeon for the pathologist. All peritoneal or Fallopian tube biopsies suspicious for peritoneal metastases must be presented to the pathologist. The peritoneal cytology results must be determined. The uterus specimen must be examined for peritoneal infiltration. Together the surgeon and pathologist need to make a decision regarding the subsequent risk of the individual patient for peritoneal metastases. If there is a risk, peritonectomy of selected anatomic sites may be required. Also, HIPEC or HIPEC plus EPIC administration requires an intraoperative judgment to proceed. In addition, prior consent for these interventions are required. By cryostat sections, the histopathological information needs to be available in the operating theater to administer the individualized treatments that are indicated in a timely manner.
3.5 CRS and HIPEC failures despite treatment
In the patient in this case report, the small bowel and its mesentery were observed to be free of peritoneal metastases. This is a favorable observation that indicates long-term success may be possible even with large masses of tumor distributed on the parietal peritoneum. Cytoreduction of small bowel and its mesentery is especially difficult. Extensive resection of small bowel is to be avoided. Also, tumor nodule removal on the bowel surface places the patient at risk for postoperative fistula. Removal of tumor from the mesentery creates a risk for small bowel ischemia. This is a major concern if tumor nodules are at the junction of small bowel with its mesentery. The mechanism for persistence and then subsequent progression of peritoneal metastases on visceral peritoneum has not been elucidated. However, incomplete resection combined with rapid removal of cancer chemotherapy with a generous blood supply within the small bowel may combine to cause the poor result. Small bowel sparing is important to the long-term success of CRS and HIPEC.
3.6 Bidirectional chemotherapy with HIPEC and EPIC for prevention or treatment of resected endometrial cancer with peritoneal metastases
For the chemotherapy agents used in this patient with peritoneal metastases from endometrial cancer, drugs with known response for this disease were selected. For HIPEC, the intraperitoneal drugs were moderate dose cisplatin and doxorubicin. Both of these drugs have activity for endometrial cancer and both are augmented in their cytotoxicity by heat. Both drugs have a favorable area under the curve ratio of intraperitoneal to systemic drug concentration. They are both acute phase agents and produce their full cytotoxic effect within the 90-minute HIPEC treatment [14]. A single systemic agent is ifosfamide. Our pharmacologic studies show that the same concentrations of intravenous and intraperitoneal ifosfamide are present almost immediately after intravenous infusion [15]. The intravenous ifosfamide has been shown to gain access to peritoneal tumor nodules.
For EPIC, paclitaxel was selected. This drug has a prolonged dwell time within the peritoneal space because of its large molecular weight. Also, it is a non-vesicant drug and well tolerated by the peritoneum without causing fibrosis [16]. Markman and coworkers demonstrated a 61% complete response rate in 28 patients with microscopic residual disease [17].
Declaration of Competing Interest
Paul H. Sugarbaker has no conflicts of interest to declare.
Funding
Data management and secretarial support provided by Foundation for Applied Research in Gastrointestinal Oncology.
Ethical approval
MedStar Health Institutional Review Board has determined that a case report of less than three (3) patients does not meet the DHHS definition of research (45 CFR 46.102(d)(pre-2018)/45 CFR46.102(l)(1/19/2017)) or the FDA definition of clinical investigation (21 CFR 46.102(c)) and therefore are not subject to IRB review requirements and do not require IRB approval.
Consent
Written and signed consent was obtained from the patient.
Author contribution
Paul H. Sugarbaker: study concept or design, data collection, data analysis or interpretation, writing the paper.
Registration of research studies
This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
Guarantor
Paul H. Sugarbaker, MD
Provenance and peer review
Not commissioned, externally peer-reviewed. | Intraperitoneal | DrugAdministrationRoute | CC BY-NC-ND | 33667906 | 19,025,392 | 2021-03 |
What was the dosage of drug 'DOXORUBICIN'? | Survival of large volume recurrent endometrial cancer with peritoneal metastases treated by cytoreductive surgery, HIPEC and EPIC. Report of a case.
Endometrial cancer may disseminate through lymphatic channels to pelvic and retroperitoneal lymph nodes, through the bloodstream to the lungs, or through the peritoneal space to peritoneal surfaces. However, not all endometrial cancers involve all 3 sites for metastatic disease.
METHODS
A patient with large volume of symptomatic recurrence of peritoneal metastases from endometrial cancer was subjected to additional surgery and both regional and systemic chemotherapy. All aspects of her disease and its treatment were studied.
The primary malignancy was treated by a laparoscopic hysterectomy and bilateral salpingo-oophorectomy followed by intravaginal radiation. Large volume recurrent disease limited to the abdomen and pelvis was treated by complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC). After recovery from surgery, systemic chemotherapy with cisplatin and paclitaxel was administered. The patient is now 25 months following treatment for recurrent cancer and free of disease.
CONCLUSIONS
The possibility of complete resection of recurrent endometrial cancer combined with HIPEC, EPIC and systemic chemotherapy is a treatment option for selected patients.
1 Introduction
Endometrial cancer is confined to the corpus uteri at the time of diagnosis in a large majority of patients [1,2]. Also, most of these patients are cured of disease by hysterectomy with or without pelvic and para-aortic lymph node dissection. Radiation therapy, usually recommended in the past, is less frequently or not used at all [3]. Combination chemotherapy is increasingly used by systemic administration. A regional (intraperitoneal chemotherapy) treatment has seldom been used in the past. This lack of enthusiasm for a regional route of administration may be questioned in that the most common sites of disease dissemination in patients thought to have uterine-confine disease is the peritoneal space. Positive peritoneal cytology was documented in 12%, 5% had adnexal involvement and 6% had gross intraperitoneal metastases [4]. These patients with early peritoneal disease at the time of primary resection will most commonly fail treatment within the peritoneal cavity [5]. Therapies may be individualized by determining the most likely sites for metastatic disease documented by careful follow-up [6].
Although not mentioned in the standard textbooks, surgery for recurrent endometrial cancer has been reported with some success. Papadia and coworkers reported a 5-year disease-free survival of 42% in 42 patients with optimal cytoreduction [7]. Cornali and coworkers added HIPEC with cisplatin to a cytoreductive surgery for 33 patients with peritoneal metastases from recurrent endometrial cancer. The 5-year overall survival was 30% (median survival was 33.1 months) [8]. The completeness of cytoreduction was the only significant factor independently influencing overall survival (p = 0.016). Goere et al. reported on 20 patients who underwent CRS and HIPEC for recurrent endometrial cancer [9].
In this case report, a patient with extensive recurrent endometrial cancer confined to the abdomen and pelvis was treated with a complete CRS, multiagent HIPEC and EPIC paclitaxel. She remains disease-free at 25 months after her intervention for recurrent disease. The ramifications of this outcome for patients who have a high propensity for progression of peritoneal metastases is discussed.
2 Patient presentation
Data on this patient was prospectively recorded and then retrospectively reviewed at an academic institution. This research work has been reported in line with the SCARE 2020 criteria [10]. This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
September 2016: At age 57, this woman developed postmenopausal bleeding. A Pap smear revealed malignant cells.
January 2017: A laparoscopic total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed by a gynecologic oncologist. Right and left sentinel pelvic lymph nodes were negative as were biopsies from right and left para-aortic lymph nodes. The endometrioid adenocarcinoma of the endometrium was FIGO grade 2 of 3. The tumor size was 3.5 cm in diameter. The histologic type was endometrioid adenocarcinoma with focal squamous differentiation. The patient underwent 5 cycles of intravaginal chemotherapy.
September 2018: The patient had an episode of urinary retention with severe discomfort upon urination. A CT scan showed disease within the greater omentum (Fig. 1), a mass associated with the transverse colon (Fig. 2) and a nodule between right and left common iliac vessels thought to be a para-aortic lymph node (Fig. 3).Fig. 1 CT scan through the upper abdomen shows cancer infiltration of the greater omentum.
Fig. 1
Fig. 2 At the level of the umbilicus, CT shows an 8 cm mass associated with the mid-transverse colon. No bowel obstruction is evident.
Fig. 2
Fig. 3 A nodule interpreted as a lymph node at the bifurcation of the aorta is seen between the right and left common iliac vessels.
Fig. 3
An encounter summary performed in the Cancer Institute recorded no drug history, no family history of cancer, and a totally normal psychosocial history.
Physical examination showed a prominent mass in the left upper quadrant which extended transversely along the abdominal wall. On pelvic exam, there were masses on the left side of the pelvis and at the apex of the vagina.
The results of the evaluation for recurrent endometrial cancer including the masses by physical examination and the marked progression of disease by CT were discussed with the patient. The possible options for treatment were discussed at a combined surgical oncology/gynecologic oncology multidisciplinary team (MDT) meeting. Given the patient’s young age and lack of comorbid conditions, a reoperative surgery plus HIPEC was recommended. This information was again, at a separate visit, communicated to the patient and her family. The possibility for adverse events and their incidence were discussed. The patient elected to move toward the cytoreductive surgery which was scheduled within 10 days. The patient was treated as part of an ongoing performance improvement project with extensive data monitoring.
October 2018: An 11-h cytoreductive surgery was performed with HIPEC by a surgical oncologist (PHS). Procedures performed included greater omentectomy, splenectomy, cholecystectomy, lesser omentectomy, peritonectomy of the undersurface of the right hemidiaphragm, partial peritonectomy of the left hemidiaphragm, transverse colectomy with anastomosis, pelvic peritonectomy and bilateral ureterolysis. The apex of the vagina was resected for approximately 4 cm because of disease at that site [11]. All specimens except the gallbladder were positive for metastatic high-grade carcinoma. The nodule at the bifurcation of the aorta was removed and submitted as a separate specimen. It was a nodule of high-grade carcinoma but was not thought to be within a lymph node. Fig. 4 shows the peritoneal cancer index.Fig. 4 The peritoneal cancer index (PCI). The PCI combines size and distribution parameters to determine a numerical score. The lesion size (LS) is used to quantitate the size of the peritoneal nodules with the 13 abdomino-pelvic regions. LS-0 indicates no tumor seen, LS-1 indicates tumor implants up to 0.5 cm, LS-2 indicates tumor implants between 0.5 and 5 cm, and LS-3 indicates tumor implants larger than 5 cm or a layering of cancer. The PCI in a 59-year-old woman undergoing surgery for recurrent endometrial high-grade carcinoma is shown in the diagram. The PCI was 20.
Fig. 4
The patient received hyperthermic intraperitoneal chemotherapy for 90 min with cisplatin 80 mg, doxorubicin 24 mg, and intravenous ifosfamide 2080 mg. Mesna was given prior to ifosfamide infusion, 4 h after completion of chemotherapy and 8 h after completion of chemotherapy at 416 mg. Temperature within the peritoneal space was approximately 42.5–43.5 °C [12].
Postoperatively, the patient received EPIC paclitaxel at 32 mg/day in 1 L of hetastarch solution for 5 consecutive days. The total dose of paclitaxel was 160 mg [12]. The patient developed a wound infection which was treated with antibiotics and opening of the lower 3 cm of the abdominal incision. The patient was discharged on her 21st postoperative day. There were no class 3 or 4 adverse events. The HIPEC and EPIC were well tolerated.
The patient received 5 cycles of systemic chemotherapy using cisplatin and paclitaxel delivered by a medical oncologist. A planned sixth cycle of systemic chemotherapy was withheld because of cumulative cisplatin toxicity.
Postoperatively, CT have been performed on a 6 monthly basis.
At 25 months postoperatively, a CT scan of the chest, abdomen and pelvis showed no progression of disease. CA-125 tumor marker was negative prior to surgery and has not shown elevation. The patient is maintained on oral nutrition without supplements and is maintaining here preoperative weight. No pain medicines are required.
3 Discussion
3.1 Treatment and prevention of peritoneal spread is possible
This case report illustrates that peritoneal metastases from endometrial cancer, even of large volume, can be controlled with a combination of complete resection and combined regional and systemic chemotherapy. Other reports attempt to convey the same message [8,9]. It is important to realize that the timing of the two components of this treatment strategy are crucial to its success. The surgery must remove all visible evidence of disease using a combination of peritonectomy procedures and visceral resections [11]. Then before stray cancer cells have the opportunity to become fixed within a fibrinous matrix, they must be washed by a chemotherapy solution to remove them mechanically and initiate chemotherapy-induced apoptosis. The current treatment option to supplement complete cytoreduction is HIPEC or HIPEC plus EPIC as was used in this patient [12]. Success in the management of peritoneal metastases from endometrial cancer is possible.
3.2 Careful study of the primary cancer may reveal the natural history of treatment failure
As published by Creasman and coworkers in a Gynecologic Oncology Group study, positive peritoneal cytology and/or peritoneal metastases are present in approximately 20% of primary endometrial cancers. The extent of the peritoneal spread and its documentation is not available from the pathologist for approximately one week following the surgical procedure. Morrow and coworkers have suggested that there is a relationship between the surgical-pathologic risk factors and the patient’s outcome [13]. Also, Mariani and coworkers more specifically showed that the findings within the resected endometrial cancer specimen can predict later progression of peritoneal metastases [5]. If CRS and HIPEC were utilized to eliminate peritoneal dissemination in patients at high risk for this type of treatment failure, an improved outcome is expected.
3.3 A new and expanded role for the pathologist in patients with endometrial cancer
Currently, a large amount of crucial information regarding the outcome of cancer patients is provided by the pathologist. The resected specimen is placed in formalin to be prosected by the pathologist at a later and convenient time. For interventions that occur at the time of cancer resection, such as CRS and HIPEC, this information is “after the fact.” Of course, very interesting, but not of benefit to the patient who may be in need of preventative treatment for subsequent progression of peritoneal disease. For peritonectomy procedures to be used to resect peritoneal metastases at a particular site, the anatomic site of disease must be documented histopathologically in the operating theater. Return to perform a second-look at a later time is not a realistic plan. Also, results of peritoneal cytology are needed while the patient is in the operating room to make a decision regarding HIPEC or HIPEC with EPIC.
3.4 Intraoperative surgical-pathological collaboration
In order to make the prediction of high risk for peritoneal recurrence/progression relevant to an individual patient, information must be made available in the operating theater. Immediately after the specimen is removed, it must be oriented by the surgeon for the pathologist. All peritoneal or Fallopian tube biopsies suspicious for peritoneal metastases must be presented to the pathologist. The peritoneal cytology results must be determined. The uterus specimen must be examined for peritoneal infiltration. Together the surgeon and pathologist need to make a decision regarding the subsequent risk of the individual patient for peritoneal metastases. If there is a risk, peritonectomy of selected anatomic sites may be required. Also, HIPEC or HIPEC plus EPIC administration requires an intraoperative judgment to proceed. In addition, prior consent for these interventions are required. By cryostat sections, the histopathological information needs to be available in the operating theater to administer the individualized treatments that are indicated in a timely manner.
3.5 CRS and HIPEC failures despite treatment
In the patient in this case report, the small bowel and its mesentery were observed to be free of peritoneal metastases. This is a favorable observation that indicates long-term success may be possible even with large masses of tumor distributed on the parietal peritoneum. Cytoreduction of small bowel and its mesentery is especially difficult. Extensive resection of small bowel is to be avoided. Also, tumor nodule removal on the bowel surface places the patient at risk for postoperative fistula. Removal of tumor from the mesentery creates a risk for small bowel ischemia. This is a major concern if tumor nodules are at the junction of small bowel with its mesentery. The mechanism for persistence and then subsequent progression of peritoneal metastases on visceral peritoneum has not been elucidated. However, incomplete resection combined with rapid removal of cancer chemotherapy with a generous blood supply within the small bowel may combine to cause the poor result. Small bowel sparing is important to the long-term success of CRS and HIPEC.
3.6 Bidirectional chemotherapy with HIPEC and EPIC for prevention or treatment of resected endometrial cancer with peritoneal metastases
For the chemotherapy agents used in this patient with peritoneal metastases from endometrial cancer, drugs with known response for this disease were selected. For HIPEC, the intraperitoneal drugs were moderate dose cisplatin and doxorubicin. Both of these drugs have activity for endometrial cancer and both are augmented in their cytotoxicity by heat. Both drugs have a favorable area under the curve ratio of intraperitoneal to systemic drug concentration. They are both acute phase agents and produce their full cytotoxic effect within the 90-minute HIPEC treatment [14]. A single systemic agent is ifosfamide. Our pharmacologic studies show that the same concentrations of intravenous and intraperitoneal ifosfamide are present almost immediately after intravenous infusion [15]. The intravenous ifosfamide has been shown to gain access to peritoneal tumor nodules.
For EPIC, paclitaxel was selected. This drug has a prolonged dwell time within the peritoneal space because of its large molecular weight. Also, it is a non-vesicant drug and well tolerated by the peritoneum without causing fibrosis [16]. Markman and coworkers demonstrated a 61% complete response rate in 28 patients with microscopic residual disease [17].
Declaration of Competing Interest
Paul H. Sugarbaker has no conflicts of interest to declare.
Funding
Data management and secretarial support provided by Foundation for Applied Research in Gastrointestinal Oncology.
Ethical approval
MedStar Health Institutional Review Board has determined that a case report of less than three (3) patients does not meet the DHHS definition of research (45 CFR 46.102(d)(pre-2018)/45 CFR46.102(l)(1/19/2017)) or the FDA definition of clinical investigation (21 CFR 46.102(c)) and therefore are not subject to IRB review requirements and do not require IRB approval.
Consent
Written and signed consent was obtained from the patient.
Author contribution
Paul H. Sugarbaker: study concept or design, data collection, data analysis or interpretation, writing the paper.
Registration of research studies
This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
Guarantor
Paul H. Sugarbaker, MD
Provenance and peer review
Not commissioned, externally peer-reviewed. | 24 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33667906 | 19,025,392 | 2021-03 |
What was the dosage of drug 'IFOSFAMIDE'? | Survival of large volume recurrent endometrial cancer with peritoneal metastases treated by cytoreductive surgery, HIPEC and EPIC. Report of a case.
Endometrial cancer may disseminate through lymphatic channels to pelvic and retroperitoneal lymph nodes, through the bloodstream to the lungs, or through the peritoneal space to peritoneal surfaces. However, not all endometrial cancers involve all 3 sites for metastatic disease.
METHODS
A patient with large volume of symptomatic recurrence of peritoneal metastases from endometrial cancer was subjected to additional surgery and both regional and systemic chemotherapy. All aspects of her disease and its treatment were studied.
The primary malignancy was treated by a laparoscopic hysterectomy and bilateral salpingo-oophorectomy followed by intravaginal radiation. Large volume recurrent disease limited to the abdomen and pelvis was treated by complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC). After recovery from surgery, systemic chemotherapy with cisplatin and paclitaxel was administered. The patient is now 25 months following treatment for recurrent cancer and free of disease.
CONCLUSIONS
The possibility of complete resection of recurrent endometrial cancer combined with HIPEC, EPIC and systemic chemotherapy is a treatment option for selected patients.
1 Introduction
Endometrial cancer is confined to the corpus uteri at the time of diagnosis in a large majority of patients [1,2]. Also, most of these patients are cured of disease by hysterectomy with or without pelvic and para-aortic lymph node dissection. Radiation therapy, usually recommended in the past, is less frequently or not used at all [3]. Combination chemotherapy is increasingly used by systemic administration. A regional (intraperitoneal chemotherapy) treatment has seldom been used in the past. This lack of enthusiasm for a regional route of administration may be questioned in that the most common sites of disease dissemination in patients thought to have uterine-confine disease is the peritoneal space. Positive peritoneal cytology was documented in 12%, 5% had adnexal involvement and 6% had gross intraperitoneal metastases [4]. These patients with early peritoneal disease at the time of primary resection will most commonly fail treatment within the peritoneal cavity [5]. Therapies may be individualized by determining the most likely sites for metastatic disease documented by careful follow-up [6].
Although not mentioned in the standard textbooks, surgery for recurrent endometrial cancer has been reported with some success. Papadia and coworkers reported a 5-year disease-free survival of 42% in 42 patients with optimal cytoreduction [7]. Cornali and coworkers added HIPEC with cisplatin to a cytoreductive surgery for 33 patients with peritoneal metastases from recurrent endometrial cancer. The 5-year overall survival was 30% (median survival was 33.1 months) [8]. The completeness of cytoreduction was the only significant factor independently influencing overall survival (p = 0.016). Goere et al. reported on 20 patients who underwent CRS and HIPEC for recurrent endometrial cancer [9].
In this case report, a patient with extensive recurrent endometrial cancer confined to the abdomen and pelvis was treated with a complete CRS, multiagent HIPEC and EPIC paclitaxel. She remains disease-free at 25 months after her intervention for recurrent disease. The ramifications of this outcome for patients who have a high propensity for progression of peritoneal metastases is discussed.
2 Patient presentation
Data on this patient was prospectively recorded and then retrospectively reviewed at an academic institution. This research work has been reported in line with the SCARE 2020 criteria [10]. This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
September 2016: At age 57, this woman developed postmenopausal bleeding. A Pap smear revealed malignant cells.
January 2017: A laparoscopic total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed by a gynecologic oncologist. Right and left sentinel pelvic lymph nodes were negative as were biopsies from right and left para-aortic lymph nodes. The endometrioid adenocarcinoma of the endometrium was FIGO grade 2 of 3. The tumor size was 3.5 cm in diameter. The histologic type was endometrioid adenocarcinoma with focal squamous differentiation. The patient underwent 5 cycles of intravaginal chemotherapy.
September 2018: The patient had an episode of urinary retention with severe discomfort upon urination. A CT scan showed disease within the greater omentum (Fig. 1), a mass associated with the transverse colon (Fig. 2) and a nodule between right and left common iliac vessels thought to be a para-aortic lymph node (Fig. 3).Fig. 1 CT scan through the upper abdomen shows cancer infiltration of the greater omentum.
Fig. 1
Fig. 2 At the level of the umbilicus, CT shows an 8 cm mass associated with the mid-transverse colon. No bowel obstruction is evident.
Fig. 2
Fig. 3 A nodule interpreted as a lymph node at the bifurcation of the aorta is seen between the right and left common iliac vessels.
Fig. 3
An encounter summary performed in the Cancer Institute recorded no drug history, no family history of cancer, and a totally normal psychosocial history.
Physical examination showed a prominent mass in the left upper quadrant which extended transversely along the abdominal wall. On pelvic exam, there were masses on the left side of the pelvis and at the apex of the vagina.
The results of the evaluation for recurrent endometrial cancer including the masses by physical examination and the marked progression of disease by CT were discussed with the patient. The possible options for treatment were discussed at a combined surgical oncology/gynecologic oncology multidisciplinary team (MDT) meeting. Given the patient’s young age and lack of comorbid conditions, a reoperative surgery plus HIPEC was recommended. This information was again, at a separate visit, communicated to the patient and her family. The possibility for adverse events and their incidence were discussed. The patient elected to move toward the cytoreductive surgery which was scheduled within 10 days. The patient was treated as part of an ongoing performance improvement project with extensive data monitoring.
October 2018: An 11-h cytoreductive surgery was performed with HIPEC by a surgical oncologist (PHS). Procedures performed included greater omentectomy, splenectomy, cholecystectomy, lesser omentectomy, peritonectomy of the undersurface of the right hemidiaphragm, partial peritonectomy of the left hemidiaphragm, transverse colectomy with anastomosis, pelvic peritonectomy and bilateral ureterolysis. The apex of the vagina was resected for approximately 4 cm because of disease at that site [11]. All specimens except the gallbladder were positive for metastatic high-grade carcinoma. The nodule at the bifurcation of the aorta was removed and submitted as a separate specimen. It was a nodule of high-grade carcinoma but was not thought to be within a lymph node. Fig. 4 shows the peritoneal cancer index.Fig. 4 The peritoneal cancer index (PCI). The PCI combines size and distribution parameters to determine a numerical score. The lesion size (LS) is used to quantitate the size of the peritoneal nodules with the 13 abdomino-pelvic regions. LS-0 indicates no tumor seen, LS-1 indicates tumor implants up to 0.5 cm, LS-2 indicates tumor implants between 0.5 and 5 cm, and LS-3 indicates tumor implants larger than 5 cm or a layering of cancer. The PCI in a 59-year-old woman undergoing surgery for recurrent endometrial high-grade carcinoma is shown in the diagram. The PCI was 20.
Fig. 4
The patient received hyperthermic intraperitoneal chemotherapy for 90 min with cisplatin 80 mg, doxorubicin 24 mg, and intravenous ifosfamide 2080 mg. Mesna was given prior to ifosfamide infusion, 4 h after completion of chemotherapy and 8 h after completion of chemotherapy at 416 mg. Temperature within the peritoneal space was approximately 42.5–43.5 °C [12].
Postoperatively, the patient received EPIC paclitaxel at 32 mg/day in 1 L of hetastarch solution for 5 consecutive days. The total dose of paclitaxel was 160 mg [12]. The patient developed a wound infection which was treated with antibiotics and opening of the lower 3 cm of the abdominal incision. The patient was discharged on her 21st postoperative day. There were no class 3 or 4 adverse events. The HIPEC and EPIC were well tolerated.
The patient received 5 cycles of systemic chemotherapy using cisplatin and paclitaxel delivered by a medical oncologist. A planned sixth cycle of systemic chemotherapy was withheld because of cumulative cisplatin toxicity.
Postoperatively, CT have been performed on a 6 monthly basis.
At 25 months postoperatively, a CT scan of the chest, abdomen and pelvis showed no progression of disease. CA-125 tumor marker was negative prior to surgery and has not shown elevation. The patient is maintained on oral nutrition without supplements and is maintaining here preoperative weight. No pain medicines are required.
3 Discussion
3.1 Treatment and prevention of peritoneal spread is possible
This case report illustrates that peritoneal metastases from endometrial cancer, even of large volume, can be controlled with a combination of complete resection and combined regional and systemic chemotherapy. Other reports attempt to convey the same message [8,9]. It is important to realize that the timing of the two components of this treatment strategy are crucial to its success. The surgery must remove all visible evidence of disease using a combination of peritonectomy procedures and visceral resections [11]. Then before stray cancer cells have the opportunity to become fixed within a fibrinous matrix, they must be washed by a chemotherapy solution to remove them mechanically and initiate chemotherapy-induced apoptosis. The current treatment option to supplement complete cytoreduction is HIPEC or HIPEC plus EPIC as was used in this patient [12]. Success in the management of peritoneal metastases from endometrial cancer is possible.
3.2 Careful study of the primary cancer may reveal the natural history of treatment failure
As published by Creasman and coworkers in a Gynecologic Oncology Group study, positive peritoneal cytology and/or peritoneal metastases are present in approximately 20% of primary endometrial cancers. The extent of the peritoneal spread and its documentation is not available from the pathologist for approximately one week following the surgical procedure. Morrow and coworkers have suggested that there is a relationship between the surgical-pathologic risk factors and the patient’s outcome [13]. Also, Mariani and coworkers more specifically showed that the findings within the resected endometrial cancer specimen can predict later progression of peritoneal metastases [5]. If CRS and HIPEC were utilized to eliminate peritoneal dissemination in patients at high risk for this type of treatment failure, an improved outcome is expected.
3.3 A new and expanded role for the pathologist in patients with endometrial cancer
Currently, a large amount of crucial information regarding the outcome of cancer patients is provided by the pathologist. The resected specimen is placed in formalin to be prosected by the pathologist at a later and convenient time. For interventions that occur at the time of cancer resection, such as CRS and HIPEC, this information is “after the fact.” Of course, very interesting, but not of benefit to the patient who may be in need of preventative treatment for subsequent progression of peritoneal disease. For peritonectomy procedures to be used to resect peritoneal metastases at a particular site, the anatomic site of disease must be documented histopathologically in the operating theater. Return to perform a second-look at a later time is not a realistic plan. Also, results of peritoneal cytology are needed while the patient is in the operating room to make a decision regarding HIPEC or HIPEC with EPIC.
3.4 Intraoperative surgical-pathological collaboration
In order to make the prediction of high risk for peritoneal recurrence/progression relevant to an individual patient, information must be made available in the operating theater. Immediately after the specimen is removed, it must be oriented by the surgeon for the pathologist. All peritoneal or Fallopian tube biopsies suspicious for peritoneal metastases must be presented to the pathologist. The peritoneal cytology results must be determined. The uterus specimen must be examined for peritoneal infiltration. Together the surgeon and pathologist need to make a decision regarding the subsequent risk of the individual patient for peritoneal metastases. If there is a risk, peritonectomy of selected anatomic sites may be required. Also, HIPEC or HIPEC plus EPIC administration requires an intraoperative judgment to proceed. In addition, prior consent for these interventions are required. By cryostat sections, the histopathological information needs to be available in the operating theater to administer the individualized treatments that are indicated in a timely manner.
3.5 CRS and HIPEC failures despite treatment
In the patient in this case report, the small bowel and its mesentery were observed to be free of peritoneal metastases. This is a favorable observation that indicates long-term success may be possible even with large masses of tumor distributed on the parietal peritoneum. Cytoreduction of small bowel and its mesentery is especially difficult. Extensive resection of small bowel is to be avoided. Also, tumor nodule removal on the bowel surface places the patient at risk for postoperative fistula. Removal of tumor from the mesentery creates a risk for small bowel ischemia. This is a major concern if tumor nodules are at the junction of small bowel with its mesentery. The mechanism for persistence and then subsequent progression of peritoneal metastases on visceral peritoneum has not been elucidated. However, incomplete resection combined with rapid removal of cancer chemotherapy with a generous blood supply within the small bowel may combine to cause the poor result. Small bowel sparing is important to the long-term success of CRS and HIPEC.
3.6 Bidirectional chemotherapy with HIPEC and EPIC for prevention or treatment of resected endometrial cancer with peritoneal metastases
For the chemotherapy agents used in this patient with peritoneal metastases from endometrial cancer, drugs with known response for this disease were selected. For HIPEC, the intraperitoneal drugs were moderate dose cisplatin and doxorubicin. Both of these drugs have activity for endometrial cancer and both are augmented in their cytotoxicity by heat. Both drugs have a favorable area under the curve ratio of intraperitoneal to systemic drug concentration. They are both acute phase agents and produce their full cytotoxic effect within the 90-minute HIPEC treatment [14]. A single systemic agent is ifosfamide. Our pharmacologic studies show that the same concentrations of intravenous and intraperitoneal ifosfamide are present almost immediately after intravenous infusion [15]. The intravenous ifosfamide has been shown to gain access to peritoneal tumor nodules.
For EPIC, paclitaxel was selected. This drug has a prolonged dwell time within the peritoneal space because of its large molecular weight. Also, it is a non-vesicant drug and well tolerated by the peritoneum without causing fibrosis [16]. Markman and coworkers demonstrated a 61% complete response rate in 28 patients with microscopic residual disease [17].
Declaration of Competing Interest
Paul H. Sugarbaker has no conflicts of interest to declare.
Funding
Data management and secretarial support provided by Foundation for Applied Research in Gastrointestinal Oncology.
Ethical approval
MedStar Health Institutional Review Board has determined that a case report of less than three (3) patients does not meet the DHHS definition of research (45 CFR 46.102(d)(pre-2018)/45 CFR46.102(l)(1/19/2017)) or the FDA definition of clinical investigation (21 CFR 46.102(c)) and therefore are not subject to IRB review requirements and do not require IRB approval.
Consent
Written and signed consent was obtained from the patient.
Author contribution
Paul H. Sugarbaker: study concept or design, data collection, data analysis or interpretation, writing the paper.
Registration of research studies
This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
Guarantor
Paul H. Sugarbaker, MD
Provenance and peer review
Not commissioned, externally peer-reviewed. | 2080 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33667906 | 19,025,392 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenic sepsis'. | Inflammatory Breast Cancer in Men: A rare clinical case report and a literature review.
The initial misdiagnosis and delayed treatment for inflammatory breast cancer in men is brought about by its rarity and lack of readily available guidelines on pathways.
METHODS
A 78-year-old male presented to the breast clinic with an abscess and was later diagnosed with inflammatory breast cancer. He presented with an abscess and was initially treated with antibiotics. Imaging showed a large left breast mass consistent with inflammatory carcinoma with axillary lymph node involvement. Patient was started on Tamoxifen as a bridge for surgery with no response. He eventually had a mastectomy and axillary clearance with the histology confirming the diagnosis and tumour emboli in the lymphatic vessels. Chemotherapy, radiation and dual hormone therapy were included in the adjuvant treatment plan. Two episodes of neutropenic sepsis led to completing only five out of six planned chemotherapy cycles.
A review of literature and the reported cases was done by the team to contribute to the little information published about the disease and its management. The presented to the breast clinic during the height of the SARS- CoV-2 pandemic. The global impact of SARS-CoV-19 made surgical teams find ways to lessen elective lists to give way for patients affected during the pandemic.
CONCLUSIONS
Very few cases of inflammatory breast cancer have been reported in men. The diagnosis can be missed leading to delay in management. Management can be challenging and complex.
1 Introduction and importance
Breast cancer in men is a rare disease worldwide [1]. Because of this, most treatment pathways are based on results of trials on women with the diagnosis. This is further supported by the fifth version of the National Comprehensive Cancer Network Guidelines released in 2020 stating that the management of breast cancer in men and women is similar overall with special considerations pertinent to male patients [3]. Unusual presentations, more specifically breast cancer that is inflammatory in nature, poses challenges on its management. Inflammatory breast cancer is commonly associated with bad prognosis [2]. Reducing delays in diagnosis by early recognition of the disease is key. The limited data on male inflammatory breast cancer that is currently published serves only as a guide, highlighting the subtle similarities and major differences in the presentation and treatment of male inflammatory breast cancer. Interestingly, the manifestation of the condition presented in the cases currently published has not shown a definitive pattern of disease progression. This case report discusses a male patient diagnosed with inflammatory breast cancer, further supported by a literature review. The patient has given the authors the consent to discuss the case in this article, along with photos provided by the patient and those taken in the clinical setting. This case report followed the guidelines set by the SCARE criteria [18].
2 Case presentation
A 78-year-old man was referred to the one-stop breast clinic with a red, tender and hot swelling lump on his left breast with pus discharge (Fig. 1a). The condition has developed over a month before and was treated in the primary care with no improvement. He was given a two-week course of Flucloxacillin 500 mg TDS. That treatment resulted in the development of a sinus discharging pus with a residual abscess underneath. He has a history of bilateral simple gynecomastia diagnosed following a previous referral to the breast clinic three years ago. He is not diabetic, doesn’t smoke and has no family history of breast cancer. His past medical history includes Hypertension, Atrial Fibrillation, Diabetes and Hyperlipidaemia. His regular medications include Allopurinol, Amlodipine and Warfarin.Fig. 1 Photos showing disease progression (all provided by the patient for use in literature and education): (a) Taken in March 2020. (b) Taken in June 2020, about three months from starting Tamoxifen. (c) Taken in August 2020.
Fig. 1
When he was examined, the large bilateral gynecomastia was noted, and an abscess/inflammatory mass was present on the left side. At that stage, the clinician organised an ultrasound scan as a mammogram was not possible due to severe pain. Ultrasound scan showed a large abscess in the left retroareolar region (Fig. 2a). Aspiration was attempted but did not yield any fluid. He was given the advice to continue the same antibiotic treatment and another appointment was arranged for clinical reassessment of improvement of the abscess. At that point, a mammogram was performed showing shows a well-marginated, round 60 mm mass with overlying skin thickening on the left breast (Fig. 2b). The right side showed simple gynecomastia.Fig. 2 (a) Ultrasound at original presentation showing an excess of 50 mm abscess in the left retroareolar region that failed to yield any aspirate fluid. Clinical management was recommended. (b) Medio-Lateral Oblique mammographic view showing a well marginated round 60 mm mass with overlying skin thickening on the left breast. The appearances are consistent with an inflammatory left breast carcinoma.
Fig. 2
The repeat ultrasound showed an irregular vascularised hypoechoic mass measuring up to 55 mm seen to directly invade the thickened overlying skin in the area of the central left breast. Ultrasound to the left axilla further showed at least four enlarged and morphologically abnormal lymph nodes. Radiologic studies report that the appearances are consistent with an inflammatory left breast carcinoma and metastatic axillary lymph nodes.
To complete the triple assessment, a core biopsy was done for the left breast and the axillary lymph node.
The biopsy from the breast and the node showed a grade 2 Invasive ductal carcinoma, oestrogen receptor positive. The case was discussed at the MDT (Multidisciplinary team) meeting at the peak of the first wave of the Covid-19 pandemic. Due to that situation, the MDT recommended primary bridging hormone treatment, and the patient was started on Tamoxifen 20 mg tablets. This was considering the advanced nature of the disease and the diagnosis of inflammatory breast cancer. Staging investigations were organised and revealed no distant metastasis.
The plan was to downstage the tumour with the primary hormone treatment in anticipation of surgery. Three months later, the patient was seen in the clinic for reassessment following hormone treatment. There was no real response with Tamoxifen. This led to the patient being listed for mastectomy and axillary clearance (Fig. 3).Fig. 3 Photos taken on the day of surgery, five months since day of diagnosis.
Fig. 3
During the surgery performed by the patient’s consultant breast surgeon, chest wall involvement was found at the lateral area of the breast. This suggests how aggressive the tumour was as the attachment to the muscle was not visible in previous imaging. Final surgical histology revealed no cellular response (Miller and Payne grade 1) to Tamoxifen. The tumour size has increased from 60 mm on initial imaging to 90 mm. Muscle involvement was confirmed and 4 out of the 22 harvested lymph nodes contained metastases. The presence of tumour emboli was confirmed in 1–2 dermal lymphatic vessels.
At the post-operative MDT, the question of further systemic treatment was discussed. It was clear that the tumour unusually didn’t show any response to Tamoxifen. Therefore, a GnRH (Gonadotropin Releasing Hormone) analogue plus an aromatase inhibitor was recommended for adjuvant endocrine treatment as per the National Comprehensive Cancer Network Guidelines [3]. Post-mastectomy radiotherapy was recommended due to the involvement of the deep margin and axillary lymph nodes.
The MDT also recommended to discuss chemotherapy. This decision would have to be balanced against the medical comorbidities of the patient versus the definite benefit of chemotherapy in his case.
The suggestion, rationale and plans for chemotherapy were explained to the patient by the oncology team. The Fluorouracil, Epirubicin, Cyclophosphamide and Docetaxel (FEC-T) six-cycle regime, along with its pathway and risks, were discussed with the patient and he accepted the recommendations.
At the end of the fifth cycle, the team met with the patient to discuss omitting the final cycle as the patient suffered neutropenic sepsis twice. Moving forward, the patient was satisfied with the plan and agreed to proceed with Radiotherapy and dual anti-hormone treatment.
3 Literature review
Little is known about Inflammatory Breast Cancer (IBC) in men hence, diagnosis may be missed and often delayed. As in the case of females, IBC diagnosis is largely a clinical diagnosis. This accounts for the possible delay in diagnosis of this condition. Treatment for IBC in men is commonly taken after therapeutic responses seen in females diagnosed with the disease [4]. Table 1 shows the summary of reported cases of male IBC found in English literature, now accounting to 13 patients with an age range of 48–85 years old, including the current patient.Table 1 Inflammatory Breast Cancer in male.
Table 1Case No Author Age (Years) Clinical Presentation Nodal Disease at presentation Distant Metastases Tumour Biology Treatment
1 Treves [11] 66 Painless mass of the axilla Axillary None Not reported –
2 Treves [11] 72 Erythema and swelling of bilateral anterior chest wall Neck, supraclavicular and bilateral inguinal None Not reported –
3 Treves [11] 70 Erythema of left breast Axillary None Not reported –
4 Sina and Samorodin [12] 72 Erythema of bilateral anterior chest wall Axillary None Not reported –
5 Yamamoto et al. [13] 68 Erythema and swelling of left anterior chest wall Axillary Pleura Not reported Systemic chemotherapy
6 Spigel et al. [14] 48 Erythema and thickening of right breast None None Not reported Neoadjuvant chemotherapy and mastectomy
7 Skarin [15] 69 Diffuse rash of left anterior chest wall/severe back pain None Bone Not reported Hormonal therapy
8 Choueiri et al. [16] 56 Neck swelling/ warmth of the right anterior chest wall/gynecomastia None None ER (-), PR (-), HER2/neu (-) Systemic chemotherapy
9 Morita et al. [6] 72 Erythema of the right chest wall/right breast mass Axillary None ER (-), PR (-) Mastectomy and adjuvant chemotherapy with radiation
10 Hyakudomi et al. [5] 85 Erythema and induration of the right chest wall Axillary Bone ER (-), PR (-), HER2/neu (-) Systemic Chemotherapy
11 Loewen et al. [4] 51 Erythema and peau ‘d orange of right breast Axillary and bilateral cervical chain Contralateral supraclavicular ER (+), PR (+), HER2/neu (-) Hormone Therapy
12 Tashima et al. [17] 67 Multiple small masses of the left anterior chest wall – Skin ER (+), PR (+), HER2/neu (-) Systemic chemotherapy and radiotherapy
13 Current 78 Tender hot swelling of left breast with pus discharge Axillary None ER (+), HER2/neu (-) Mastectomy, Systemic Chemotherapy, Radiotherapy and Hormone Therapy
Generally, 92 % of male breast cancers are ER positive [1]. Out of the now 13 reported cases of inflammatory breast cancer in men, six were tested for ER, PR and HER2 expression, two of which were triple negative [1,5] and one tested for ER and PR only, turned out receptor negative [6].
This patient, who is now the 13th reported case of inflammatory breast cancer in men, is only the third hormone receptor positive reported inflammatory breast cancer case in men. The first reported ER positive patient was initially treated with Exemestane only, due to lack of medical insurance and patient’s apprehensions. At the 12-month follow up, the patient has not reported any medication intolerance and continued the treatment with Everolimus and radiation therapy [4].
The details of the systemic treatment of eight out of the first 12 cases were described in the literature. Six out of eight of these patients were given chemotherapy [5].
Of the previous cases collated, two had no data on Lymph node involvement and only one had no actual lymph node involvement. The rest, including the current case, had at least an axillary lymph node metastasis [4]. Evidently, there is still marked delay in identifying this aggressive disease causing a higher likelihood that it has already reached the lymph nodes once the diagnosis is made.
4 Discussion
Inflammatory breast cancer is said to be a clinico-pathological diagnosis [2]. What is generally agreed is its abrupt onset (no more than 6 months) with erythema involving more than a third of the breast [2]. Though pathognomonic and common in IBC, dermal lymphatic invasion was found out to be not required to establish a diagnosis [2].
Generally, for breast cancer in men, Tamoxifen is commonly used because of its efficacy in the both adjuvant and palliative settings [7]. There is no available literature to support its use in the neo-adjuvant setting and therefore the evidence is very limited.
Though Tamoxifen remains to be the first line hormone therapy for male breast cancer [7], occasions where it is not an option for treatment for men who test positive for oestrogen receptors is not unheard of. Deep vein thrombosis and weight gain are reported toxicities warranting discontinuation of the treatment [1,7]. These cause a large proportion of men to stop treatment before 5 years [1].
In men, single-agent adjuvant treatment with an aromatase inhibitor has been associated with inferior outcomes compared to Tamoxifen alone, likely due to inadequate estradiol suppression, and is not recommended [3].
This course of treatment was displayed in a case reported by Jiang et al. [8]. This was of a man who was initially treated with Letrozole as first line endocrine treatment. This was discontinued after 7 months because of disease progression. This was followed by Goserelin plus Anastrazole shortly after distant metastasis was found. This treatment provided stability of the disease for a year prior to progression. Examestane replaced Anastrazole for the next 11 months, again, providing stability before further progression [8].
The extent of muscle involvement that was seen during the mastectomy of the patient indicated adjuvant radiotherapy. Men are more likely to be offered post mastectomy chest wall radiation therapy (PMRT) due to concern of adequate surgical margins even in small tumours and the higher incidence of nipple or skin involvement [1]. A radiotherapy boost may be administered to his chest wall to address this.
The risk of gynecomastia and breast cancer coexists in high oestrogen states [9]. This association is bringing into question the likelihood of these two separate conditions to co-exist; challenging the initially proposed idea that gynecomastia increases the risk for breast cancer. The current patient still presents with gynecomastia on the contralateral side.
The global event brought about by SARS-CoV-19 affected the elective surgical activity immensely. More manpower support was needed for the critical care departments who care for patients with the coronavirus disease 2019, hence a huge number of elective surgeries were put on hold [10]. Surgical teams had to prioritise elective lists and alter treatment paths for patients who do not require immediate surgery. It can be argued that the patient could have had chemotherapy as a neo adjuvant treatment. The situation in the healthcare system at the time of presentation required a conscientious decision to attempt downstaging the tumour prior to surgery. This led to the discovery of having no response to hormone treatment, following discussion for more treatment.
5 Conclusion
The limited data that we currently have for male inflammatory breast cancer still would not sufficiently provide a standard pathway for treatment.Men will still experience delay in diagnosis and treatment due to the lack of published information and reliable treatment pathways.
This reported case and literature review aim to add to the available body of evidence available for the management of this rare clinical condition which can represent a challenge for clinicians managing breast cancer in men.
Declaration of Competing Interest
The authors report no declarations of interest.
Sources of funding
The research done for this case report was not supported by sponsors for funding.
Ethical approval
The case report does not require ethical approval.
Consent
The patient has consented to the study and reporting of his case, he has provided photos to support the endeavour and signed a consent form to document this.
Author contribution
Angeline Tanhueco: Methodology, Investigation, Resources, Writing- Original Draft Preparation, Visualisation.
Mina Youssef: Conceptualisation, Resources, Review and Editing, Supervision.
Registration of research studies
Not applicable.
Guarantor
Mr. Mina Youssef.
Provenance and peer review
Not commissioned, externally peer-reviewed. | ALLOPURINOL, AMLODIPINE BESYLATE, CYCLOPHOSPHAMIDE, DOCETAXEL, EPIRUBICIN, FLUOROURACIL, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 33667907 | 19,094,678 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy non-responder'. | Inflammatory Breast Cancer in Men: A rare clinical case report and a literature review.
The initial misdiagnosis and delayed treatment for inflammatory breast cancer in men is brought about by its rarity and lack of readily available guidelines on pathways.
METHODS
A 78-year-old male presented to the breast clinic with an abscess and was later diagnosed with inflammatory breast cancer. He presented with an abscess and was initially treated with antibiotics. Imaging showed a large left breast mass consistent with inflammatory carcinoma with axillary lymph node involvement. Patient was started on Tamoxifen as a bridge for surgery with no response. He eventually had a mastectomy and axillary clearance with the histology confirming the diagnosis and tumour emboli in the lymphatic vessels. Chemotherapy, radiation and dual hormone therapy were included in the adjuvant treatment plan. Two episodes of neutropenic sepsis led to completing only five out of six planned chemotherapy cycles.
A review of literature and the reported cases was done by the team to contribute to the little information published about the disease and its management. The presented to the breast clinic during the height of the SARS- CoV-2 pandemic. The global impact of SARS-CoV-19 made surgical teams find ways to lessen elective lists to give way for patients affected during the pandemic.
CONCLUSIONS
Very few cases of inflammatory breast cancer have been reported in men. The diagnosis can be missed leading to delay in management. Management can be challenging and complex.
1 Introduction and importance
Breast cancer in men is a rare disease worldwide [1]. Because of this, most treatment pathways are based on results of trials on women with the diagnosis. This is further supported by the fifth version of the National Comprehensive Cancer Network Guidelines released in 2020 stating that the management of breast cancer in men and women is similar overall with special considerations pertinent to male patients [3]. Unusual presentations, more specifically breast cancer that is inflammatory in nature, poses challenges on its management. Inflammatory breast cancer is commonly associated with bad prognosis [2]. Reducing delays in diagnosis by early recognition of the disease is key. The limited data on male inflammatory breast cancer that is currently published serves only as a guide, highlighting the subtle similarities and major differences in the presentation and treatment of male inflammatory breast cancer. Interestingly, the manifestation of the condition presented in the cases currently published has not shown a definitive pattern of disease progression. This case report discusses a male patient diagnosed with inflammatory breast cancer, further supported by a literature review. The patient has given the authors the consent to discuss the case in this article, along with photos provided by the patient and those taken in the clinical setting. This case report followed the guidelines set by the SCARE criteria [18].
2 Case presentation
A 78-year-old man was referred to the one-stop breast clinic with a red, tender and hot swelling lump on his left breast with pus discharge (Fig. 1a). The condition has developed over a month before and was treated in the primary care with no improvement. He was given a two-week course of Flucloxacillin 500 mg TDS. That treatment resulted in the development of a sinus discharging pus with a residual abscess underneath. He has a history of bilateral simple gynecomastia diagnosed following a previous referral to the breast clinic three years ago. He is not diabetic, doesn’t smoke and has no family history of breast cancer. His past medical history includes Hypertension, Atrial Fibrillation, Diabetes and Hyperlipidaemia. His regular medications include Allopurinol, Amlodipine and Warfarin.Fig. 1 Photos showing disease progression (all provided by the patient for use in literature and education): (a) Taken in March 2020. (b) Taken in June 2020, about three months from starting Tamoxifen. (c) Taken in August 2020.
Fig. 1
When he was examined, the large bilateral gynecomastia was noted, and an abscess/inflammatory mass was present on the left side. At that stage, the clinician organised an ultrasound scan as a mammogram was not possible due to severe pain. Ultrasound scan showed a large abscess in the left retroareolar region (Fig. 2a). Aspiration was attempted but did not yield any fluid. He was given the advice to continue the same antibiotic treatment and another appointment was arranged for clinical reassessment of improvement of the abscess. At that point, a mammogram was performed showing shows a well-marginated, round 60 mm mass with overlying skin thickening on the left breast (Fig. 2b). The right side showed simple gynecomastia.Fig. 2 (a) Ultrasound at original presentation showing an excess of 50 mm abscess in the left retroareolar region that failed to yield any aspirate fluid. Clinical management was recommended. (b) Medio-Lateral Oblique mammographic view showing a well marginated round 60 mm mass with overlying skin thickening on the left breast. The appearances are consistent with an inflammatory left breast carcinoma.
Fig. 2
The repeat ultrasound showed an irregular vascularised hypoechoic mass measuring up to 55 mm seen to directly invade the thickened overlying skin in the area of the central left breast. Ultrasound to the left axilla further showed at least four enlarged and morphologically abnormal lymph nodes. Radiologic studies report that the appearances are consistent with an inflammatory left breast carcinoma and metastatic axillary lymph nodes.
To complete the triple assessment, a core biopsy was done for the left breast and the axillary lymph node.
The biopsy from the breast and the node showed a grade 2 Invasive ductal carcinoma, oestrogen receptor positive. The case was discussed at the MDT (Multidisciplinary team) meeting at the peak of the first wave of the Covid-19 pandemic. Due to that situation, the MDT recommended primary bridging hormone treatment, and the patient was started on Tamoxifen 20 mg tablets. This was considering the advanced nature of the disease and the diagnosis of inflammatory breast cancer. Staging investigations were organised and revealed no distant metastasis.
The plan was to downstage the tumour with the primary hormone treatment in anticipation of surgery. Three months later, the patient was seen in the clinic for reassessment following hormone treatment. There was no real response with Tamoxifen. This led to the patient being listed for mastectomy and axillary clearance (Fig. 3).Fig. 3 Photos taken on the day of surgery, five months since day of diagnosis.
Fig. 3
During the surgery performed by the patient’s consultant breast surgeon, chest wall involvement was found at the lateral area of the breast. This suggests how aggressive the tumour was as the attachment to the muscle was not visible in previous imaging. Final surgical histology revealed no cellular response (Miller and Payne grade 1) to Tamoxifen. The tumour size has increased from 60 mm on initial imaging to 90 mm. Muscle involvement was confirmed and 4 out of the 22 harvested lymph nodes contained metastases. The presence of tumour emboli was confirmed in 1–2 dermal lymphatic vessels.
At the post-operative MDT, the question of further systemic treatment was discussed. It was clear that the tumour unusually didn’t show any response to Tamoxifen. Therefore, a GnRH (Gonadotropin Releasing Hormone) analogue plus an aromatase inhibitor was recommended for adjuvant endocrine treatment as per the National Comprehensive Cancer Network Guidelines [3]. Post-mastectomy radiotherapy was recommended due to the involvement of the deep margin and axillary lymph nodes.
The MDT also recommended to discuss chemotherapy. This decision would have to be balanced against the medical comorbidities of the patient versus the definite benefit of chemotherapy in his case.
The suggestion, rationale and plans for chemotherapy were explained to the patient by the oncology team. The Fluorouracil, Epirubicin, Cyclophosphamide and Docetaxel (FEC-T) six-cycle regime, along with its pathway and risks, were discussed with the patient and he accepted the recommendations.
At the end of the fifth cycle, the team met with the patient to discuss omitting the final cycle as the patient suffered neutropenic sepsis twice. Moving forward, the patient was satisfied with the plan and agreed to proceed with Radiotherapy and dual anti-hormone treatment.
3 Literature review
Little is known about Inflammatory Breast Cancer (IBC) in men hence, diagnosis may be missed and often delayed. As in the case of females, IBC diagnosis is largely a clinical diagnosis. This accounts for the possible delay in diagnosis of this condition. Treatment for IBC in men is commonly taken after therapeutic responses seen in females diagnosed with the disease [4]. Table 1 shows the summary of reported cases of male IBC found in English literature, now accounting to 13 patients with an age range of 48–85 years old, including the current patient.Table 1 Inflammatory Breast Cancer in male.
Table 1Case No Author Age (Years) Clinical Presentation Nodal Disease at presentation Distant Metastases Tumour Biology Treatment
1 Treves [11] 66 Painless mass of the axilla Axillary None Not reported –
2 Treves [11] 72 Erythema and swelling of bilateral anterior chest wall Neck, supraclavicular and bilateral inguinal None Not reported –
3 Treves [11] 70 Erythema of left breast Axillary None Not reported –
4 Sina and Samorodin [12] 72 Erythema of bilateral anterior chest wall Axillary None Not reported –
5 Yamamoto et al. [13] 68 Erythema and swelling of left anterior chest wall Axillary Pleura Not reported Systemic chemotherapy
6 Spigel et al. [14] 48 Erythema and thickening of right breast None None Not reported Neoadjuvant chemotherapy and mastectomy
7 Skarin [15] 69 Diffuse rash of left anterior chest wall/severe back pain None Bone Not reported Hormonal therapy
8 Choueiri et al. [16] 56 Neck swelling/ warmth of the right anterior chest wall/gynecomastia None None ER (-), PR (-), HER2/neu (-) Systemic chemotherapy
9 Morita et al. [6] 72 Erythema of the right chest wall/right breast mass Axillary None ER (-), PR (-) Mastectomy and adjuvant chemotherapy with radiation
10 Hyakudomi et al. [5] 85 Erythema and induration of the right chest wall Axillary Bone ER (-), PR (-), HER2/neu (-) Systemic Chemotherapy
11 Loewen et al. [4] 51 Erythema and peau ‘d orange of right breast Axillary and bilateral cervical chain Contralateral supraclavicular ER (+), PR (+), HER2/neu (-) Hormone Therapy
12 Tashima et al. [17] 67 Multiple small masses of the left anterior chest wall – Skin ER (+), PR (+), HER2/neu (-) Systemic chemotherapy and radiotherapy
13 Current 78 Tender hot swelling of left breast with pus discharge Axillary None ER (+), HER2/neu (-) Mastectomy, Systemic Chemotherapy, Radiotherapy and Hormone Therapy
Generally, 92 % of male breast cancers are ER positive [1]. Out of the now 13 reported cases of inflammatory breast cancer in men, six were tested for ER, PR and HER2 expression, two of which were triple negative [1,5] and one tested for ER and PR only, turned out receptor negative [6].
This patient, who is now the 13th reported case of inflammatory breast cancer in men, is only the third hormone receptor positive reported inflammatory breast cancer case in men. The first reported ER positive patient was initially treated with Exemestane only, due to lack of medical insurance and patient’s apprehensions. At the 12-month follow up, the patient has not reported any medication intolerance and continued the treatment with Everolimus and radiation therapy [4].
The details of the systemic treatment of eight out of the first 12 cases were described in the literature. Six out of eight of these patients were given chemotherapy [5].
Of the previous cases collated, two had no data on Lymph node involvement and only one had no actual lymph node involvement. The rest, including the current case, had at least an axillary lymph node metastasis [4]. Evidently, there is still marked delay in identifying this aggressive disease causing a higher likelihood that it has already reached the lymph nodes once the diagnosis is made.
4 Discussion
Inflammatory breast cancer is said to be a clinico-pathological diagnosis [2]. What is generally agreed is its abrupt onset (no more than 6 months) with erythema involving more than a third of the breast [2]. Though pathognomonic and common in IBC, dermal lymphatic invasion was found out to be not required to establish a diagnosis [2].
Generally, for breast cancer in men, Tamoxifen is commonly used because of its efficacy in the both adjuvant and palliative settings [7]. There is no available literature to support its use in the neo-adjuvant setting and therefore the evidence is very limited.
Though Tamoxifen remains to be the first line hormone therapy for male breast cancer [7], occasions where it is not an option for treatment for men who test positive for oestrogen receptors is not unheard of. Deep vein thrombosis and weight gain are reported toxicities warranting discontinuation of the treatment [1,7]. These cause a large proportion of men to stop treatment before 5 years [1].
In men, single-agent adjuvant treatment with an aromatase inhibitor has been associated with inferior outcomes compared to Tamoxifen alone, likely due to inadequate estradiol suppression, and is not recommended [3].
This course of treatment was displayed in a case reported by Jiang et al. [8]. This was of a man who was initially treated with Letrozole as first line endocrine treatment. This was discontinued after 7 months because of disease progression. This was followed by Goserelin plus Anastrazole shortly after distant metastasis was found. This treatment provided stability of the disease for a year prior to progression. Examestane replaced Anastrazole for the next 11 months, again, providing stability before further progression [8].
The extent of muscle involvement that was seen during the mastectomy of the patient indicated adjuvant radiotherapy. Men are more likely to be offered post mastectomy chest wall radiation therapy (PMRT) due to concern of adequate surgical margins even in small tumours and the higher incidence of nipple or skin involvement [1]. A radiotherapy boost may be administered to his chest wall to address this.
The risk of gynecomastia and breast cancer coexists in high oestrogen states [9]. This association is bringing into question the likelihood of these two separate conditions to co-exist; challenging the initially proposed idea that gynecomastia increases the risk for breast cancer. The current patient still presents with gynecomastia on the contralateral side.
The global event brought about by SARS-CoV-19 affected the elective surgical activity immensely. More manpower support was needed for the critical care departments who care for patients with the coronavirus disease 2019, hence a huge number of elective surgeries were put on hold [10]. Surgical teams had to prioritise elective lists and alter treatment paths for patients who do not require immediate surgery. It can be argued that the patient could have had chemotherapy as a neo adjuvant treatment. The situation in the healthcare system at the time of presentation required a conscientious decision to attempt downstaging the tumour prior to surgery. This led to the discovery of having no response to hormone treatment, following discussion for more treatment.
5 Conclusion
The limited data that we currently have for male inflammatory breast cancer still would not sufficiently provide a standard pathway for treatment.Men will still experience delay in diagnosis and treatment due to the lack of published information and reliable treatment pathways.
This reported case and literature review aim to add to the available body of evidence available for the management of this rare clinical condition which can represent a challenge for clinicians managing breast cancer in men.
Declaration of Competing Interest
The authors report no declarations of interest.
Sources of funding
The research done for this case report was not supported by sponsors for funding.
Ethical approval
The case report does not require ethical approval.
Consent
The patient has consented to the study and reporting of his case, he has provided photos to support the endeavour and signed a consent form to document this.
Author contribution
Angeline Tanhueco: Methodology, Investigation, Resources, Writing- Original Draft Preparation, Visualisation.
Mina Youssef: Conceptualisation, Resources, Review and Editing, Supervision.
Registration of research studies
Not applicable.
Guarantor
Mr. Mina Youssef.
Provenance and peer review
Not commissioned, externally peer-reviewed. | ALLOPURINOL, AMLODIPINE BESYLATE, TAMOXIFEN, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 33667907 | 19,168,253 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.
BACKGROUND
We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).
METHODS
We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.
RESULTS
n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.
CONCLUSIONS
Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
1. Introduction
Safinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].
Depression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.
Concerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.
The aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.
2. Materials and Methods
2.1. Study Design and Population
This was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.
The sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.
The primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.
As for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.
To test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].
Levodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].
2.2. Statistical Analyzsis
The demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.
3. Results
We enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.
The doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.
3.1. Effect of Safinamide on Depression in PD Patients
The primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).
3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice
In the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).
3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events
The relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.
Finally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.
4. Discussion
Safinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.
Although robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.
Based on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].
We found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].
We must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.
5. Conclusions
Safinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.
Acknowledgments
This is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.
Author Contributions
Conceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.
Funding
This study was funded by Zambon.
Institutional Review Board Statement
Ethical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.
Informed Consent Statement
Informed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Esteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.
Figure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.
brainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).
n n (%) Complete cohort 82
Safinamide-only group 38 (46.3%)
Safinamide + antidepressants group 44 (53.7%)
Age (years) Mean (SD) [range] Complete cohort 68.33 (11.41) [41–90]
Ssafinamide-only group 70.13 (9.83) [41–87]
Safinamide + antidepressants group 66.77 (12.51) [42–90]
Gender (male/female) n (%)/n (%) Complete cohort 37 (45.1%)/45 (54.9%)
Safinamide-only group 21 (55.3%)/17 (44.7%)
Safinamide + antidepressants group 16 (36.4%)/28 (63.6%)
Disease duration (years) Mean (SD) Complete cohort 8.67 (8.55)
Safinamide-only group 7.84 (9.65)
Safinamide + antidepressants group 9.39 (7.51)
UPDRS
I Mean (SD) Complete cohort 4.56 (1.82)
Safinamide-only group 3.82 (1.90)
Safinamide + antidepressants group 5.20 (1.49)
II Mean (SD) Complete cohort 13.59 (6.67)
Safinamide-only group 13.55 (7.07)
Safinamide + antidepressants group 13.61 (6.38)
III Mean (SD) Complete cohort 22.91 (8.68)
Safinamide-only group 22.47 (9.90)
Safinamide + antidepressants group 23.30 (7.57)
IV Mean (SD) Complete cohort 3.51 (2.83)
Safinamide-only group 2.61 (2.52)
Safinamide + antidepressants group 4.30 (2.87)
HAMD-17 Mean (SD) Complete cohort 19.49 (4.03)
Safinamide-only group 18.39 (3.58)
Safinamide + antidepressants group 20.43 (4.20)
LEDD (mg) Mean (SD) Complete cohort 810.26 (368.45)
Safinamide-only group 681.25 (218.15)
Safinamide + antidepressants group 921.68 (432.86)
UPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.
brainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.
Antidepressant Drug Range of Doses (mg/day) n (%)
DULOXETINE 30–120 11 (25.0%)
ESCITALOPRAM 5–15 7 (15.9%)
MIRTAZAPINE 15–30 5 (11.4%)
SERTRALINE 50–100 5 (11.4%)
VENLAFAXINE 75–150 5 (11.4%)
TRAZODONE 50–100 4 (9.1%)
AMITRIPTILINE 25 1 (2.3%)
CLORIMIPRAMINE 25 1 (2.3%)
BUPROPION 150 1 (2.3%)
CITALOPRAM 20 1 (2.3%)
PAROXETINE + AMITRIPTILINE 10 + 25 1 (2.3%)
VENLAFAXINE + MIRTAZAPINE 75 + 15 1 (2.3%)
VORTIOXETINE 10 1 (2.3%)
brainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.
Baseline
Mean (SD) 1 Month
Mean Difference from Baseline (SD) p-Value 3 Months
Mean Difference from Baseline (SD) p-Value
HAMD-17 Complete cohort 19.49 (4.03)
n = 82 −6 (5.10)
n = 78 p < 0.0001 −7.27 (5.48)
n = 82 p < 0.0001
Safinamide 50 mg 18.50 (2.69)
n = 22 −3.32 (4.54)
n = 22 p = 0.0003 −4.73 (4.49)
n = 22 p < 0.0001
Safinamide 100 mg 19.85 (4.39)
n = 60 −7.03 (5.19)
n = 56 p < 0.0001 −8.02 (5.73)
n = 60 p < 0.0001
UPDRS I Complete cohort 4.56 (1.82)
n = 82 −1.32 (1.99)
n = 78 p < 0.0001 −1.5 (2.03)
n = 82 p < 0.0001
Safinamide 50 mg 4.59 (1.47)
n = 22 −0.64 (1.91)
n = 22 p = 0.0157 −0.91 (1.76)
n = 22 p = 0.0045
Safinamide 100 mg 4.55 (1.94)
n = 60 −1.59 (1.97)
n = 56 p < 0.0001 −1.72 (2.08)
n = 60 p < 0.0001
UPDRS II Complete cohort 13.59 (6.67)
n = 82 −2.51 (6.30)
n = 78 p < 0.0001 −2.47 (6.11)
n = 82 p < 0.0001
Safinamide 50 mg 11.50 (5.20)
n = 22 −0.36 (5.44)
n = 22 p = 0.4064 −0.23 (5.23)
n = 22 p = 0.4966
Safinamide 100 mg 14.35 (7.02)
n = 60 −3.30 (6.65)
n = 56 p < 0.0001 −3.28 (6.45)
n = 60 p < 0.0001
UPDRS III Complete cohort 22.91 (8.68)
n = 82 −3.58 (8.56)
n = 78 p < 0.0001 −4.03 (8.95)
n = 82 p < 0.0001
Safinamide 50 mg 22.00 (8.12)
n = 22 −0.41 (8.88)
n = 22 p = 0.7722 +0.50 (9.42)
n = 22 p = 0.6723
Safinamide 100 mg 23.25 (8.92)
n = 60 −4.8 (8.34)
n= 56 p < 0.0001 −5.70 (8.47)
n = 60 p < 0.0001
UPDRS IV Complete cohort 3.51 (2.83)
n = 82 −0.61 (2.61)
n = 78 p = 0.0003 −0.8 (2.53)
n = 82 p < 0.0001
Safinamide 50 mg 4.64 (2.59)
n = 22 −0.32 (2.38)
n = 22 p = 0.1839 −0.28 (2.50)
n = 22 p = 0.2482
Safinamide 100 mg 3.10 (2.82)
n = 60 −0.76 (2.50)
n = 56 p = 0.0007 −1.00 (2.28)
n = 60 p < 0.0001
HAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.
brainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.
1 Month 3 Months
Safinamide + Antidepressants Group
n = 42 Safinamide-only Group
n = 36 p-Value Safinamide + Antidepressants Group
n = 44 Safinamide-only Group
n = 38 p-Value
Major symptoms Confusion n (%) 2 (2.6%) 0 (0%) p = 0.564 1 (1.2%) 0 (0%) p = 1.251
Emotional lability 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 1 (1.2%) p = 0.627
Fever 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Sweating 3 (3.8%) 1 (1.3%) p = 0.627 3 (3.7%) 0 (0%) p = 0.266
Myoclonus 0 (0%) 0 (0%) - 2 (2.4%) 0 (0%) p = 0.565
Minor symptoms Agitation n (%) 2 (2.6%) 1 (1.3%) p = 1.021 1 (1.2%) 0 (0%) p = 1.251
Sleep disorders 13 (16.7%) 4 (5.1%) p = 0.053 13 (15.9%) 4 (4.9%) p = 0.054
Nervousness 15 (19.2%) 4 (5.1%) p = 0.017 13 (15.9%) 5 (6.1%) p = 0.108
Tachycardia 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 0 (0%) p = 0.266
Hyperventilation 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Dyspnea 1 (1.3%) 2 (2.6%) p = 0.642 2 (2.4%) 3 (3.7%) p = 0.666
Diarrhea 0 (0%) 1 (1.3%) p = 0.897 1 (1.2%) 0 (0%) p = 1.251
Hypertension 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Hypotension 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Ataxia 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Data were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | SAFINAMIDE, SERTRALINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33668408 | 19,139,499 | 2021-02-13 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug interaction'. | Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.
BACKGROUND
We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).
METHODS
We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.
RESULTS
n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.
CONCLUSIONS
Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
1. Introduction
Safinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].
Depression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.
Concerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.
The aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.
2. Materials and Methods
2.1. Study Design and Population
This was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.
The sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.
The primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.
As for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.
To test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].
Levodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].
2.2. Statistical Analyzsis
The demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.
3. Results
We enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.
The doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.
3.1. Effect of Safinamide on Depression in PD Patients
The primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).
3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice
In the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).
3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events
The relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.
Finally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.
4. Discussion
Safinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.
Although robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.
Based on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].
We found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].
We must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.
5. Conclusions
Safinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.
Acknowledgments
This is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.
Author Contributions
Conceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.
Funding
This study was funded by Zambon.
Institutional Review Board Statement
Ethical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.
Informed Consent Statement
Informed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Esteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.
Figure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.
brainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).
n n (%) Complete cohort 82
Safinamide-only group 38 (46.3%)
Safinamide + antidepressants group 44 (53.7%)
Age (years) Mean (SD) [range] Complete cohort 68.33 (11.41) [41–90]
Ssafinamide-only group 70.13 (9.83) [41–87]
Safinamide + antidepressants group 66.77 (12.51) [42–90]
Gender (male/female) n (%)/n (%) Complete cohort 37 (45.1%)/45 (54.9%)
Safinamide-only group 21 (55.3%)/17 (44.7%)
Safinamide + antidepressants group 16 (36.4%)/28 (63.6%)
Disease duration (years) Mean (SD) Complete cohort 8.67 (8.55)
Safinamide-only group 7.84 (9.65)
Safinamide + antidepressants group 9.39 (7.51)
UPDRS
I Mean (SD) Complete cohort 4.56 (1.82)
Safinamide-only group 3.82 (1.90)
Safinamide + antidepressants group 5.20 (1.49)
II Mean (SD) Complete cohort 13.59 (6.67)
Safinamide-only group 13.55 (7.07)
Safinamide + antidepressants group 13.61 (6.38)
III Mean (SD) Complete cohort 22.91 (8.68)
Safinamide-only group 22.47 (9.90)
Safinamide + antidepressants group 23.30 (7.57)
IV Mean (SD) Complete cohort 3.51 (2.83)
Safinamide-only group 2.61 (2.52)
Safinamide + antidepressants group 4.30 (2.87)
HAMD-17 Mean (SD) Complete cohort 19.49 (4.03)
Safinamide-only group 18.39 (3.58)
Safinamide + antidepressants group 20.43 (4.20)
LEDD (mg) Mean (SD) Complete cohort 810.26 (368.45)
Safinamide-only group 681.25 (218.15)
Safinamide + antidepressants group 921.68 (432.86)
UPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.
brainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.
Antidepressant Drug Range of Doses (mg/day) n (%)
DULOXETINE 30–120 11 (25.0%)
ESCITALOPRAM 5–15 7 (15.9%)
MIRTAZAPINE 15–30 5 (11.4%)
SERTRALINE 50–100 5 (11.4%)
VENLAFAXINE 75–150 5 (11.4%)
TRAZODONE 50–100 4 (9.1%)
AMITRIPTILINE 25 1 (2.3%)
CLORIMIPRAMINE 25 1 (2.3%)
BUPROPION 150 1 (2.3%)
CITALOPRAM 20 1 (2.3%)
PAROXETINE + AMITRIPTILINE 10 + 25 1 (2.3%)
VENLAFAXINE + MIRTAZAPINE 75 + 15 1 (2.3%)
VORTIOXETINE 10 1 (2.3%)
brainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.
Baseline
Mean (SD) 1 Month
Mean Difference from Baseline (SD) p-Value 3 Months
Mean Difference from Baseline (SD) p-Value
HAMD-17 Complete cohort 19.49 (4.03)
n = 82 −6 (5.10)
n = 78 p < 0.0001 −7.27 (5.48)
n = 82 p < 0.0001
Safinamide 50 mg 18.50 (2.69)
n = 22 −3.32 (4.54)
n = 22 p = 0.0003 −4.73 (4.49)
n = 22 p < 0.0001
Safinamide 100 mg 19.85 (4.39)
n = 60 −7.03 (5.19)
n = 56 p < 0.0001 −8.02 (5.73)
n = 60 p < 0.0001
UPDRS I Complete cohort 4.56 (1.82)
n = 82 −1.32 (1.99)
n = 78 p < 0.0001 −1.5 (2.03)
n = 82 p < 0.0001
Safinamide 50 mg 4.59 (1.47)
n = 22 −0.64 (1.91)
n = 22 p = 0.0157 −0.91 (1.76)
n = 22 p = 0.0045
Safinamide 100 mg 4.55 (1.94)
n = 60 −1.59 (1.97)
n = 56 p < 0.0001 −1.72 (2.08)
n = 60 p < 0.0001
UPDRS II Complete cohort 13.59 (6.67)
n = 82 −2.51 (6.30)
n = 78 p < 0.0001 −2.47 (6.11)
n = 82 p < 0.0001
Safinamide 50 mg 11.50 (5.20)
n = 22 −0.36 (5.44)
n = 22 p = 0.4064 −0.23 (5.23)
n = 22 p = 0.4966
Safinamide 100 mg 14.35 (7.02)
n = 60 −3.30 (6.65)
n = 56 p < 0.0001 −3.28 (6.45)
n = 60 p < 0.0001
UPDRS III Complete cohort 22.91 (8.68)
n = 82 −3.58 (8.56)
n = 78 p < 0.0001 −4.03 (8.95)
n = 82 p < 0.0001
Safinamide 50 mg 22.00 (8.12)
n = 22 −0.41 (8.88)
n = 22 p = 0.7722 +0.50 (9.42)
n = 22 p = 0.6723
Safinamide 100 mg 23.25 (8.92)
n = 60 −4.8 (8.34)
n= 56 p < 0.0001 −5.70 (8.47)
n = 60 p < 0.0001
UPDRS IV Complete cohort 3.51 (2.83)
n = 82 −0.61 (2.61)
n = 78 p = 0.0003 −0.8 (2.53)
n = 82 p < 0.0001
Safinamide 50 mg 4.64 (2.59)
n = 22 −0.32 (2.38)
n = 22 p = 0.1839 −0.28 (2.50)
n = 22 p = 0.2482
Safinamide 100 mg 3.10 (2.82)
n = 60 −0.76 (2.50)
n = 56 p = 0.0007 −1.00 (2.28)
n = 60 p < 0.0001
HAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.
brainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.
1 Month 3 Months
Safinamide + Antidepressants Group
n = 42 Safinamide-only Group
n = 36 p-Value Safinamide + Antidepressants Group
n = 44 Safinamide-only Group
n = 38 p-Value
Major symptoms Confusion n (%) 2 (2.6%) 0 (0%) p = 0.564 1 (1.2%) 0 (0%) p = 1.251
Emotional lability 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 1 (1.2%) p = 0.627
Fever 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Sweating 3 (3.8%) 1 (1.3%) p = 0.627 3 (3.7%) 0 (0%) p = 0.266
Myoclonus 0 (0%) 0 (0%) - 2 (2.4%) 0 (0%) p = 0.565
Minor symptoms Agitation n (%) 2 (2.6%) 1 (1.3%) p = 1.021 1 (1.2%) 0 (0%) p = 1.251
Sleep disorders 13 (16.7%) 4 (5.1%) p = 0.053 13 (15.9%) 4 (4.9%) p = 0.054
Nervousness 15 (19.2%) 4 (5.1%) p = 0.017 13 (15.9%) 5 (6.1%) p = 0.108
Tachycardia 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 0 (0%) p = 0.266
Hyperventilation 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Dyspnea 1 (1.3%) 2 (2.6%) p = 0.642 2 (2.4%) 3 (3.7%) p = 0.666
Diarrhea 0 (0%) 1 (1.3%) p = 0.897 1 (1.2%) 0 (0%) p = 1.251
Hypertension 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Hypotension 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Ataxia 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Data were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | SAFINAMIDE, SERTRALINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33668408 | 19,366,789 | 2021-02-13 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Labelled drug-drug interaction issue'. | Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.
BACKGROUND
We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).
METHODS
We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.
RESULTS
n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.
CONCLUSIONS
Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
1. Introduction
Safinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].
Depression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.
Concerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.
The aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.
2. Materials and Methods
2.1. Study Design and Population
This was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.
The sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.
The primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.
As for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.
To test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].
Levodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].
2.2. Statistical Analyzsis
The demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.
3. Results
We enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.
The doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.
3.1. Effect of Safinamide on Depression in PD Patients
The primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).
3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice
In the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).
3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events
The relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.
Finally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.
4. Discussion
Safinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.
Although robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.
Based on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].
We found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].
We must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.
5. Conclusions
Safinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.
Acknowledgments
This is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.
Author Contributions
Conceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.
Funding
This study was funded by Zambon.
Institutional Review Board Statement
Ethical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.
Informed Consent Statement
Informed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Esteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.
Figure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.
brainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).
n n (%) Complete cohort 82
Safinamide-only group 38 (46.3%)
Safinamide + antidepressants group 44 (53.7%)
Age (years) Mean (SD) [range] Complete cohort 68.33 (11.41) [41–90]
Ssafinamide-only group 70.13 (9.83) [41–87]
Safinamide + antidepressants group 66.77 (12.51) [42–90]
Gender (male/female) n (%)/n (%) Complete cohort 37 (45.1%)/45 (54.9%)
Safinamide-only group 21 (55.3%)/17 (44.7%)
Safinamide + antidepressants group 16 (36.4%)/28 (63.6%)
Disease duration (years) Mean (SD) Complete cohort 8.67 (8.55)
Safinamide-only group 7.84 (9.65)
Safinamide + antidepressants group 9.39 (7.51)
UPDRS
I Mean (SD) Complete cohort 4.56 (1.82)
Safinamide-only group 3.82 (1.90)
Safinamide + antidepressants group 5.20 (1.49)
II Mean (SD) Complete cohort 13.59 (6.67)
Safinamide-only group 13.55 (7.07)
Safinamide + antidepressants group 13.61 (6.38)
III Mean (SD) Complete cohort 22.91 (8.68)
Safinamide-only group 22.47 (9.90)
Safinamide + antidepressants group 23.30 (7.57)
IV Mean (SD) Complete cohort 3.51 (2.83)
Safinamide-only group 2.61 (2.52)
Safinamide + antidepressants group 4.30 (2.87)
HAMD-17 Mean (SD) Complete cohort 19.49 (4.03)
Safinamide-only group 18.39 (3.58)
Safinamide + antidepressants group 20.43 (4.20)
LEDD (mg) Mean (SD) Complete cohort 810.26 (368.45)
Safinamide-only group 681.25 (218.15)
Safinamide + antidepressants group 921.68 (432.86)
UPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.
brainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.
Antidepressant Drug Range of Doses (mg/day) n (%)
DULOXETINE 30–120 11 (25.0%)
ESCITALOPRAM 5–15 7 (15.9%)
MIRTAZAPINE 15–30 5 (11.4%)
SERTRALINE 50–100 5 (11.4%)
VENLAFAXINE 75–150 5 (11.4%)
TRAZODONE 50–100 4 (9.1%)
AMITRIPTILINE 25 1 (2.3%)
CLORIMIPRAMINE 25 1 (2.3%)
BUPROPION 150 1 (2.3%)
CITALOPRAM 20 1 (2.3%)
PAROXETINE + AMITRIPTILINE 10 + 25 1 (2.3%)
VENLAFAXINE + MIRTAZAPINE 75 + 15 1 (2.3%)
VORTIOXETINE 10 1 (2.3%)
brainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.
Baseline
Mean (SD) 1 Month
Mean Difference from Baseline (SD) p-Value 3 Months
Mean Difference from Baseline (SD) p-Value
HAMD-17 Complete cohort 19.49 (4.03)
n = 82 −6 (5.10)
n = 78 p < 0.0001 −7.27 (5.48)
n = 82 p < 0.0001
Safinamide 50 mg 18.50 (2.69)
n = 22 −3.32 (4.54)
n = 22 p = 0.0003 −4.73 (4.49)
n = 22 p < 0.0001
Safinamide 100 mg 19.85 (4.39)
n = 60 −7.03 (5.19)
n = 56 p < 0.0001 −8.02 (5.73)
n = 60 p < 0.0001
UPDRS I Complete cohort 4.56 (1.82)
n = 82 −1.32 (1.99)
n = 78 p < 0.0001 −1.5 (2.03)
n = 82 p < 0.0001
Safinamide 50 mg 4.59 (1.47)
n = 22 −0.64 (1.91)
n = 22 p = 0.0157 −0.91 (1.76)
n = 22 p = 0.0045
Safinamide 100 mg 4.55 (1.94)
n = 60 −1.59 (1.97)
n = 56 p < 0.0001 −1.72 (2.08)
n = 60 p < 0.0001
UPDRS II Complete cohort 13.59 (6.67)
n = 82 −2.51 (6.30)
n = 78 p < 0.0001 −2.47 (6.11)
n = 82 p < 0.0001
Safinamide 50 mg 11.50 (5.20)
n = 22 −0.36 (5.44)
n = 22 p = 0.4064 −0.23 (5.23)
n = 22 p = 0.4966
Safinamide 100 mg 14.35 (7.02)
n = 60 −3.30 (6.65)
n = 56 p < 0.0001 −3.28 (6.45)
n = 60 p < 0.0001
UPDRS III Complete cohort 22.91 (8.68)
n = 82 −3.58 (8.56)
n = 78 p < 0.0001 −4.03 (8.95)
n = 82 p < 0.0001
Safinamide 50 mg 22.00 (8.12)
n = 22 −0.41 (8.88)
n = 22 p = 0.7722 +0.50 (9.42)
n = 22 p = 0.6723
Safinamide 100 mg 23.25 (8.92)
n = 60 −4.8 (8.34)
n= 56 p < 0.0001 −5.70 (8.47)
n = 60 p < 0.0001
UPDRS IV Complete cohort 3.51 (2.83)
n = 82 −0.61 (2.61)
n = 78 p = 0.0003 −0.8 (2.53)
n = 82 p < 0.0001
Safinamide 50 mg 4.64 (2.59)
n = 22 −0.32 (2.38)
n = 22 p = 0.1839 −0.28 (2.50)
n = 22 p = 0.2482
Safinamide 100 mg 3.10 (2.82)
n = 60 −0.76 (2.50)
n = 56 p = 0.0007 −1.00 (2.28)
n = 60 p < 0.0001
HAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.
brainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.
1 Month 3 Months
Safinamide + Antidepressants Group
n = 42 Safinamide-only Group
n = 36 p-Value Safinamide + Antidepressants Group
n = 44 Safinamide-only Group
n = 38 p-Value
Major symptoms Confusion n (%) 2 (2.6%) 0 (0%) p = 0.564 1 (1.2%) 0 (0%) p = 1.251
Emotional lability 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 1 (1.2%) p = 0.627
Fever 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Sweating 3 (3.8%) 1 (1.3%) p = 0.627 3 (3.7%) 0 (0%) p = 0.266
Myoclonus 0 (0%) 0 (0%) - 2 (2.4%) 0 (0%) p = 0.565
Minor symptoms Agitation n (%) 2 (2.6%) 1 (1.3%) p = 1.021 1 (1.2%) 0 (0%) p = 1.251
Sleep disorders 13 (16.7%) 4 (5.1%) p = 0.053 13 (15.9%) 4 (4.9%) p = 0.054
Nervousness 15 (19.2%) 4 (5.1%) p = 0.017 13 (15.9%) 5 (6.1%) p = 0.108
Tachycardia 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 0 (0%) p = 0.266
Hyperventilation 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Dyspnea 1 (1.3%) 2 (2.6%) p = 0.642 2 (2.4%) 3 (3.7%) p = 0.666
Diarrhea 0 (0%) 1 (1.3%) p = 0.897 1 (1.2%) 0 (0%) p = 1.251
Hypertension 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Hypotension 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Ataxia 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Data were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | DULOXETINE, SAFINAMIDE, TRAMADOL | DrugsGivenReaction | CC BY | 33668408 | 19,167,920 | 2021-02-13 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myoclonus'. | Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.
BACKGROUND
We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).
METHODS
We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.
RESULTS
n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.
CONCLUSIONS
Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
1. Introduction
Safinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].
Depression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.
Concerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.
The aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.
2. Materials and Methods
2.1. Study Design and Population
This was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.
The sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.
The primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.
As for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.
To test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].
Levodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].
2.2. Statistical Analyzsis
The demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.
3. Results
We enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.
The doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.
3.1. Effect of Safinamide on Depression in PD Patients
The primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).
3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice
In the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).
3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events
The relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.
Finally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.
4. Discussion
Safinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.
Although robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.
Based on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].
We found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].
We must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.
5. Conclusions
Safinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.
Acknowledgments
This is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.
Author Contributions
Conceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.
Funding
This study was funded by Zambon.
Institutional Review Board Statement
Ethical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.
Informed Consent Statement
Informed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Esteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.
Figure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.
brainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).
n n (%) Complete cohort 82
Safinamide-only group 38 (46.3%)
Safinamide + antidepressants group 44 (53.7%)
Age (years) Mean (SD) [range] Complete cohort 68.33 (11.41) [41–90]
Ssafinamide-only group 70.13 (9.83) [41–87]
Safinamide + antidepressants group 66.77 (12.51) [42–90]
Gender (male/female) n (%)/n (%) Complete cohort 37 (45.1%)/45 (54.9%)
Safinamide-only group 21 (55.3%)/17 (44.7%)
Safinamide + antidepressants group 16 (36.4%)/28 (63.6%)
Disease duration (years) Mean (SD) Complete cohort 8.67 (8.55)
Safinamide-only group 7.84 (9.65)
Safinamide + antidepressants group 9.39 (7.51)
UPDRS
I Mean (SD) Complete cohort 4.56 (1.82)
Safinamide-only group 3.82 (1.90)
Safinamide + antidepressants group 5.20 (1.49)
II Mean (SD) Complete cohort 13.59 (6.67)
Safinamide-only group 13.55 (7.07)
Safinamide + antidepressants group 13.61 (6.38)
III Mean (SD) Complete cohort 22.91 (8.68)
Safinamide-only group 22.47 (9.90)
Safinamide + antidepressants group 23.30 (7.57)
IV Mean (SD) Complete cohort 3.51 (2.83)
Safinamide-only group 2.61 (2.52)
Safinamide + antidepressants group 4.30 (2.87)
HAMD-17 Mean (SD) Complete cohort 19.49 (4.03)
Safinamide-only group 18.39 (3.58)
Safinamide + antidepressants group 20.43 (4.20)
LEDD (mg) Mean (SD) Complete cohort 810.26 (368.45)
Safinamide-only group 681.25 (218.15)
Safinamide + antidepressants group 921.68 (432.86)
UPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.
brainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.
Antidepressant Drug Range of Doses (mg/day) n (%)
DULOXETINE 30–120 11 (25.0%)
ESCITALOPRAM 5–15 7 (15.9%)
MIRTAZAPINE 15–30 5 (11.4%)
SERTRALINE 50–100 5 (11.4%)
VENLAFAXINE 75–150 5 (11.4%)
TRAZODONE 50–100 4 (9.1%)
AMITRIPTILINE 25 1 (2.3%)
CLORIMIPRAMINE 25 1 (2.3%)
BUPROPION 150 1 (2.3%)
CITALOPRAM 20 1 (2.3%)
PAROXETINE + AMITRIPTILINE 10 + 25 1 (2.3%)
VENLAFAXINE + MIRTAZAPINE 75 + 15 1 (2.3%)
VORTIOXETINE 10 1 (2.3%)
brainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.
Baseline
Mean (SD) 1 Month
Mean Difference from Baseline (SD) p-Value 3 Months
Mean Difference from Baseline (SD) p-Value
HAMD-17 Complete cohort 19.49 (4.03)
n = 82 −6 (5.10)
n = 78 p < 0.0001 −7.27 (5.48)
n = 82 p < 0.0001
Safinamide 50 mg 18.50 (2.69)
n = 22 −3.32 (4.54)
n = 22 p = 0.0003 −4.73 (4.49)
n = 22 p < 0.0001
Safinamide 100 mg 19.85 (4.39)
n = 60 −7.03 (5.19)
n = 56 p < 0.0001 −8.02 (5.73)
n = 60 p < 0.0001
UPDRS I Complete cohort 4.56 (1.82)
n = 82 −1.32 (1.99)
n = 78 p < 0.0001 −1.5 (2.03)
n = 82 p < 0.0001
Safinamide 50 mg 4.59 (1.47)
n = 22 −0.64 (1.91)
n = 22 p = 0.0157 −0.91 (1.76)
n = 22 p = 0.0045
Safinamide 100 mg 4.55 (1.94)
n = 60 −1.59 (1.97)
n = 56 p < 0.0001 −1.72 (2.08)
n = 60 p < 0.0001
UPDRS II Complete cohort 13.59 (6.67)
n = 82 −2.51 (6.30)
n = 78 p < 0.0001 −2.47 (6.11)
n = 82 p < 0.0001
Safinamide 50 mg 11.50 (5.20)
n = 22 −0.36 (5.44)
n = 22 p = 0.4064 −0.23 (5.23)
n = 22 p = 0.4966
Safinamide 100 mg 14.35 (7.02)
n = 60 −3.30 (6.65)
n = 56 p < 0.0001 −3.28 (6.45)
n = 60 p < 0.0001
UPDRS III Complete cohort 22.91 (8.68)
n = 82 −3.58 (8.56)
n = 78 p < 0.0001 −4.03 (8.95)
n = 82 p < 0.0001
Safinamide 50 mg 22.00 (8.12)
n = 22 −0.41 (8.88)
n = 22 p = 0.7722 +0.50 (9.42)
n = 22 p = 0.6723
Safinamide 100 mg 23.25 (8.92)
n = 60 −4.8 (8.34)
n= 56 p < 0.0001 −5.70 (8.47)
n = 60 p < 0.0001
UPDRS IV Complete cohort 3.51 (2.83)
n = 82 −0.61 (2.61)
n = 78 p = 0.0003 −0.8 (2.53)
n = 82 p < 0.0001
Safinamide 50 mg 4.64 (2.59)
n = 22 −0.32 (2.38)
n = 22 p = 0.1839 −0.28 (2.50)
n = 22 p = 0.2482
Safinamide 100 mg 3.10 (2.82)
n = 60 −0.76 (2.50)
n = 56 p = 0.0007 −1.00 (2.28)
n = 60 p < 0.0001
HAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.
brainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.
1 Month 3 Months
Safinamide + Antidepressants Group
n = 42 Safinamide-only Group
n = 36 p-Value Safinamide + Antidepressants Group
n = 44 Safinamide-only Group
n = 38 p-Value
Major symptoms Confusion n (%) 2 (2.6%) 0 (0%) p = 0.564 1 (1.2%) 0 (0%) p = 1.251
Emotional lability 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 1 (1.2%) p = 0.627
Fever 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Sweating 3 (3.8%) 1 (1.3%) p = 0.627 3 (3.7%) 0 (0%) p = 0.266
Myoclonus 0 (0%) 0 (0%) - 2 (2.4%) 0 (0%) p = 0.565
Minor symptoms Agitation n (%) 2 (2.6%) 1 (1.3%) p = 1.021 1 (1.2%) 0 (0%) p = 1.251
Sleep disorders 13 (16.7%) 4 (5.1%) p = 0.053 13 (15.9%) 4 (4.9%) p = 0.054
Nervousness 15 (19.2%) 4 (5.1%) p = 0.017 13 (15.9%) 5 (6.1%) p = 0.108
Tachycardia 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 0 (0%) p = 0.266
Hyperventilation 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Dyspnea 1 (1.3%) 2 (2.6%) p = 0.642 2 (2.4%) 3 (3.7%) p = 0.666
Diarrhea 0 (0%) 1 (1.3%) p = 0.897 1 (1.2%) 0 (0%) p = 1.251
Hypertension 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Hypotension 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Ataxia 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Data were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | DULOXETINE, SAFINAMIDE, TRAMADOL | DrugsGivenReaction | CC BY | 33668408 | 19,139,897 | 2021-02-13 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nervousness'. | Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.
BACKGROUND
We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).
METHODS
We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.
RESULTS
n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.
CONCLUSIONS
Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
1. Introduction
Safinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].
Depression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.
Concerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.
The aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.
2. Materials and Methods
2.1. Study Design and Population
This was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.
The sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.
The primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.
As for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.
To test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].
Levodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].
2.2. Statistical Analyzsis
The demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.
3. Results
We enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.
The doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.
3.1. Effect of Safinamide on Depression in PD Patients
The primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).
3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice
In the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).
3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events
The relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.
Finally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.
4. Discussion
Safinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.
Although robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.
Based on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].
We found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].
We must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.
5. Conclusions
Safinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.
Acknowledgments
This is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.
Author Contributions
Conceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.
Funding
This study was funded by Zambon.
Institutional Review Board Statement
Ethical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.
Informed Consent Statement
Informed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Esteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.
Figure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.
brainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).
n n (%) Complete cohort 82
Safinamide-only group 38 (46.3%)
Safinamide + antidepressants group 44 (53.7%)
Age (years) Mean (SD) [range] Complete cohort 68.33 (11.41) [41–90]
Ssafinamide-only group 70.13 (9.83) [41–87]
Safinamide + antidepressants group 66.77 (12.51) [42–90]
Gender (male/female) n (%)/n (%) Complete cohort 37 (45.1%)/45 (54.9%)
Safinamide-only group 21 (55.3%)/17 (44.7%)
Safinamide + antidepressants group 16 (36.4%)/28 (63.6%)
Disease duration (years) Mean (SD) Complete cohort 8.67 (8.55)
Safinamide-only group 7.84 (9.65)
Safinamide + antidepressants group 9.39 (7.51)
UPDRS
I Mean (SD) Complete cohort 4.56 (1.82)
Safinamide-only group 3.82 (1.90)
Safinamide + antidepressants group 5.20 (1.49)
II Mean (SD) Complete cohort 13.59 (6.67)
Safinamide-only group 13.55 (7.07)
Safinamide + antidepressants group 13.61 (6.38)
III Mean (SD) Complete cohort 22.91 (8.68)
Safinamide-only group 22.47 (9.90)
Safinamide + antidepressants group 23.30 (7.57)
IV Mean (SD) Complete cohort 3.51 (2.83)
Safinamide-only group 2.61 (2.52)
Safinamide + antidepressants group 4.30 (2.87)
HAMD-17 Mean (SD) Complete cohort 19.49 (4.03)
Safinamide-only group 18.39 (3.58)
Safinamide + antidepressants group 20.43 (4.20)
LEDD (mg) Mean (SD) Complete cohort 810.26 (368.45)
Safinamide-only group 681.25 (218.15)
Safinamide + antidepressants group 921.68 (432.86)
UPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.
brainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.
Antidepressant Drug Range of Doses (mg/day) n (%)
DULOXETINE 30–120 11 (25.0%)
ESCITALOPRAM 5–15 7 (15.9%)
MIRTAZAPINE 15–30 5 (11.4%)
SERTRALINE 50–100 5 (11.4%)
VENLAFAXINE 75–150 5 (11.4%)
TRAZODONE 50–100 4 (9.1%)
AMITRIPTILINE 25 1 (2.3%)
CLORIMIPRAMINE 25 1 (2.3%)
BUPROPION 150 1 (2.3%)
CITALOPRAM 20 1 (2.3%)
PAROXETINE + AMITRIPTILINE 10 + 25 1 (2.3%)
VENLAFAXINE + MIRTAZAPINE 75 + 15 1 (2.3%)
VORTIOXETINE 10 1 (2.3%)
brainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.
Baseline
Mean (SD) 1 Month
Mean Difference from Baseline (SD) p-Value 3 Months
Mean Difference from Baseline (SD) p-Value
HAMD-17 Complete cohort 19.49 (4.03)
n = 82 −6 (5.10)
n = 78 p < 0.0001 −7.27 (5.48)
n = 82 p < 0.0001
Safinamide 50 mg 18.50 (2.69)
n = 22 −3.32 (4.54)
n = 22 p = 0.0003 −4.73 (4.49)
n = 22 p < 0.0001
Safinamide 100 mg 19.85 (4.39)
n = 60 −7.03 (5.19)
n = 56 p < 0.0001 −8.02 (5.73)
n = 60 p < 0.0001
UPDRS I Complete cohort 4.56 (1.82)
n = 82 −1.32 (1.99)
n = 78 p < 0.0001 −1.5 (2.03)
n = 82 p < 0.0001
Safinamide 50 mg 4.59 (1.47)
n = 22 −0.64 (1.91)
n = 22 p = 0.0157 −0.91 (1.76)
n = 22 p = 0.0045
Safinamide 100 mg 4.55 (1.94)
n = 60 −1.59 (1.97)
n = 56 p < 0.0001 −1.72 (2.08)
n = 60 p < 0.0001
UPDRS II Complete cohort 13.59 (6.67)
n = 82 −2.51 (6.30)
n = 78 p < 0.0001 −2.47 (6.11)
n = 82 p < 0.0001
Safinamide 50 mg 11.50 (5.20)
n = 22 −0.36 (5.44)
n = 22 p = 0.4064 −0.23 (5.23)
n = 22 p = 0.4966
Safinamide 100 mg 14.35 (7.02)
n = 60 −3.30 (6.65)
n = 56 p < 0.0001 −3.28 (6.45)
n = 60 p < 0.0001
UPDRS III Complete cohort 22.91 (8.68)
n = 82 −3.58 (8.56)
n = 78 p < 0.0001 −4.03 (8.95)
n = 82 p < 0.0001
Safinamide 50 mg 22.00 (8.12)
n = 22 −0.41 (8.88)
n = 22 p = 0.7722 +0.50 (9.42)
n = 22 p = 0.6723
Safinamide 100 mg 23.25 (8.92)
n = 60 −4.8 (8.34)
n= 56 p < 0.0001 −5.70 (8.47)
n = 60 p < 0.0001
UPDRS IV Complete cohort 3.51 (2.83)
n = 82 −0.61 (2.61)
n = 78 p = 0.0003 −0.8 (2.53)
n = 82 p < 0.0001
Safinamide 50 mg 4.64 (2.59)
n = 22 −0.32 (2.38)
n = 22 p = 0.1839 −0.28 (2.50)
n = 22 p = 0.2482
Safinamide 100 mg 3.10 (2.82)
n = 60 −0.76 (2.50)
n = 56 p = 0.0007 −1.00 (2.28)
n = 60 p < 0.0001
HAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.
brainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.
1 Month 3 Months
Safinamide + Antidepressants Group
n = 42 Safinamide-only Group
n = 36 p-Value Safinamide + Antidepressants Group
n = 44 Safinamide-only Group
n = 38 p-Value
Major symptoms Confusion n (%) 2 (2.6%) 0 (0%) p = 0.564 1 (1.2%) 0 (0%) p = 1.251
Emotional lability 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 1 (1.2%) p = 0.627
Fever 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Sweating 3 (3.8%) 1 (1.3%) p = 0.627 3 (3.7%) 0 (0%) p = 0.266
Myoclonus 0 (0%) 0 (0%) - 2 (2.4%) 0 (0%) p = 0.565
Minor symptoms Agitation n (%) 2 (2.6%) 1 (1.3%) p = 1.021 1 (1.2%) 0 (0%) p = 1.251
Sleep disorders 13 (16.7%) 4 (5.1%) p = 0.053 13 (15.9%) 4 (4.9%) p = 0.054
Nervousness 15 (19.2%) 4 (5.1%) p = 0.017 13 (15.9%) 5 (6.1%) p = 0.108
Tachycardia 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 0 (0%) p = 0.266
Hyperventilation 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Dyspnea 1 (1.3%) 2 (2.6%) p = 0.642 2 (2.4%) 3 (3.7%) p = 0.666
Diarrhea 0 (0%) 1 (1.3%) p = 0.897 1 (1.2%) 0 (0%) p = 1.251
Hypertension 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Hypotension 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Ataxia 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Data were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | DULOXETINE, SAFINAMIDE, TRAMADOL | DrugsGivenReaction | CC BY | 33668408 | 19,139,897 | 2021-02-13 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.
BACKGROUND
We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).
METHODS
We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.
RESULTS
n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.
CONCLUSIONS
Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
1. Introduction
Safinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].
Depression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.
Concerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.
The aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.
2. Materials and Methods
2.1. Study Design and Population
This was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.
The sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.
The primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.
As for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.
To test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].
Levodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].
2.2. Statistical Analyzsis
The demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.
3. Results
We enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.
The doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.
3.1. Effect of Safinamide on Depression in PD Patients
The primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).
3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice
In the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).
3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events
The relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.
Finally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.
4. Discussion
Safinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.
Although robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.
Based on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].
We found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].
We must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.
5. Conclusions
Safinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.
Acknowledgments
This is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.
Author Contributions
Conceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.
Funding
This study was funded by Zambon.
Institutional Review Board Statement
Ethical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.
Informed Consent Statement
Informed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Esteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.
Figure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.
brainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).
n n (%) Complete cohort 82
Safinamide-only group 38 (46.3%)
Safinamide + antidepressants group 44 (53.7%)
Age (years) Mean (SD) [range] Complete cohort 68.33 (11.41) [41–90]
Ssafinamide-only group 70.13 (9.83) [41–87]
Safinamide + antidepressants group 66.77 (12.51) [42–90]
Gender (male/female) n (%)/n (%) Complete cohort 37 (45.1%)/45 (54.9%)
Safinamide-only group 21 (55.3%)/17 (44.7%)
Safinamide + antidepressants group 16 (36.4%)/28 (63.6%)
Disease duration (years) Mean (SD) Complete cohort 8.67 (8.55)
Safinamide-only group 7.84 (9.65)
Safinamide + antidepressants group 9.39 (7.51)
UPDRS
I Mean (SD) Complete cohort 4.56 (1.82)
Safinamide-only group 3.82 (1.90)
Safinamide + antidepressants group 5.20 (1.49)
II Mean (SD) Complete cohort 13.59 (6.67)
Safinamide-only group 13.55 (7.07)
Safinamide + antidepressants group 13.61 (6.38)
III Mean (SD) Complete cohort 22.91 (8.68)
Safinamide-only group 22.47 (9.90)
Safinamide + antidepressants group 23.30 (7.57)
IV Mean (SD) Complete cohort 3.51 (2.83)
Safinamide-only group 2.61 (2.52)
Safinamide + antidepressants group 4.30 (2.87)
HAMD-17 Mean (SD) Complete cohort 19.49 (4.03)
Safinamide-only group 18.39 (3.58)
Safinamide + antidepressants group 20.43 (4.20)
LEDD (mg) Mean (SD) Complete cohort 810.26 (368.45)
Safinamide-only group 681.25 (218.15)
Safinamide + antidepressants group 921.68 (432.86)
UPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.
brainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.
Antidepressant Drug Range of Doses (mg/day) n (%)
DULOXETINE 30–120 11 (25.0%)
ESCITALOPRAM 5–15 7 (15.9%)
MIRTAZAPINE 15–30 5 (11.4%)
SERTRALINE 50–100 5 (11.4%)
VENLAFAXINE 75–150 5 (11.4%)
TRAZODONE 50–100 4 (9.1%)
AMITRIPTILINE 25 1 (2.3%)
CLORIMIPRAMINE 25 1 (2.3%)
BUPROPION 150 1 (2.3%)
CITALOPRAM 20 1 (2.3%)
PAROXETINE + AMITRIPTILINE 10 + 25 1 (2.3%)
VENLAFAXINE + MIRTAZAPINE 75 + 15 1 (2.3%)
VORTIOXETINE 10 1 (2.3%)
brainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.
Baseline
Mean (SD) 1 Month
Mean Difference from Baseline (SD) p-Value 3 Months
Mean Difference from Baseline (SD) p-Value
HAMD-17 Complete cohort 19.49 (4.03)
n = 82 −6 (5.10)
n = 78 p < 0.0001 −7.27 (5.48)
n = 82 p < 0.0001
Safinamide 50 mg 18.50 (2.69)
n = 22 −3.32 (4.54)
n = 22 p = 0.0003 −4.73 (4.49)
n = 22 p < 0.0001
Safinamide 100 mg 19.85 (4.39)
n = 60 −7.03 (5.19)
n = 56 p < 0.0001 −8.02 (5.73)
n = 60 p < 0.0001
UPDRS I Complete cohort 4.56 (1.82)
n = 82 −1.32 (1.99)
n = 78 p < 0.0001 −1.5 (2.03)
n = 82 p < 0.0001
Safinamide 50 mg 4.59 (1.47)
n = 22 −0.64 (1.91)
n = 22 p = 0.0157 −0.91 (1.76)
n = 22 p = 0.0045
Safinamide 100 mg 4.55 (1.94)
n = 60 −1.59 (1.97)
n = 56 p < 0.0001 −1.72 (2.08)
n = 60 p < 0.0001
UPDRS II Complete cohort 13.59 (6.67)
n = 82 −2.51 (6.30)
n = 78 p < 0.0001 −2.47 (6.11)
n = 82 p < 0.0001
Safinamide 50 mg 11.50 (5.20)
n = 22 −0.36 (5.44)
n = 22 p = 0.4064 −0.23 (5.23)
n = 22 p = 0.4966
Safinamide 100 mg 14.35 (7.02)
n = 60 −3.30 (6.65)
n = 56 p < 0.0001 −3.28 (6.45)
n = 60 p < 0.0001
UPDRS III Complete cohort 22.91 (8.68)
n = 82 −3.58 (8.56)
n = 78 p < 0.0001 −4.03 (8.95)
n = 82 p < 0.0001
Safinamide 50 mg 22.00 (8.12)
n = 22 −0.41 (8.88)
n = 22 p = 0.7722 +0.50 (9.42)
n = 22 p = 0.6723
Safinamide 100 mg 23.25 (8.92)
n = 60 −4.8 (8.34)
n= 56 p < 0.0001 −5.70 (8.47)
n = 60 p < 0.0001
UPDRS IV Complete cohort 3.51 (2.83)
n = 82 −0.61 (2.61)
n = 78 p = 0.0003 −0.8 (2.53)
n = 82 p < 0.0001
Safinamide 50 mg 4.64 (2.59)
n = 22 −0.32 (2.38)
n = 22 p = 0.1839 −0.28 (2.50)
n = 22 p = 0.2482
Safinamide 100 mg 3.10 (2.82)
n = 60 −0.76 (2.50)
n = 56 p = 0.0007 −1.00 (2.28)
n = 60 p < 0.0001
HAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.
brainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.
1 Month 3 Months
Safinamide + Antidepressants Group
n = 42 Safinamide-only Group
n = 36 p-Value Safinamide + Antidepressants Group
n = 44 Safinamide-only Group
n = 38 p-Value
Major symptoms Confusion n (%) 2 (2.6%) 0 (0%) p = 0.564 1 (1.2%) 0 (0%) p = 1.251
Emotional lability 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 1 (1.2%) p = 0.627
Fever 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Sweating 3 (3.8%) 1 (1.3%) p = 0.627 3 (3.7%) 0 (0%) p = 0.266
Myoclonus 0 (0%) 0 (0%) - 2 (2.4%) 0 (0%) p = 0.565
Minor symptoms Agitation n (%) 2 (2.6%) 1 (1.3%) p = 1.021 1 (1.2%) 0 (0%) p = 1.251
Sleep disorders 13 (16.7%) 4 (5.1%) p = 0.053 13 (15.9%) 4 (4.9%) p = 0.054
Nervousness 15 (19.2%) 4 (5.1%) p = 0.017 13 (15.9%) 5 (6.1%) p = 0.108
Tachycardia 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 0 (0%) p = 0.266
Hyperventilation 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Dyspnea 1 (1.3%) 2 (2.6%) p = 0.642 2 (2.4%) 3 (3.7%) p = 0.666
Diarrhea 0 (0%) 1 (1.3%) p = 0.897 1 (1.2%) 0 (0%) p = 1.251
Hypertension 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Hypotension 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Ataxia 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Data were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.
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What was the outcome of reaction 'Confusional state'? | Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.
BACKGROUND
We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).
METHODS
We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.
RESULTS
n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.
CONCLUSIONS
Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
1. Introduction
Safinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].
Depression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.
Concerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.
The aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.
2. Materials and Methods
2.1. Study Design and Population
This was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.
The sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.
The primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.
As for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.
To test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].
Levodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].
2.2. Statistical Analyzsis
The demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.
3. Results
We enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.
The doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.
3.1. Effect of Safinamide on Depression in PD Patients
The primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).
3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice
In the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).
3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events
The relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.
Finally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.
4. Discussion
Safinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.
Although robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.
Based on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].
We found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].
We must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.
5. Conclusions
Safinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.
Acknowledgments
This is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.
Author Contributions
Conceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.
Funding
This study was funded by Zambon.
Institutional Review Board Statement
Ethical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.
Informed Consent Statement
Informed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Esteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.
Figure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.
brainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).
n n (%) Complete cohort 82
Safinamide-only group 38 (46.3%)
Safinamide + antidepressants group 44 (53.7%)
Age (years) Mean (SD) [range] Complete cohort 68.33 (11.41) [41–90]
Ssafinamide-only group 70.13 (9.83) [41–87]
Safinamide + antidepressants group 66.77 (12.51) [42–90]
Gender (male/female) n (%)/n (%) Complete cohort 37 (45.1%)/45 (54.9%)
Safinamide-only group 21 (55.3%)/17 (44.7%)
Safinamide + antidepressants group 16 (36.4%)/28 (63.6%)
Disease duration (years) Mean (SD) Complete cohort 8.67 (8.55)
Safinamide-only group 7.84 (9.65)
Safinamide + antidepressants group 9.39 (7.51)
UPDRS
I Mean (SD) Complete cohort 4.56 (1.82)
Safinamide-only group 3.82 (1.90)
Safinamide + antidepressants group 5.20 (1.49)
II Mean (SD) Complete cohort 13.59 (6.67)
Safinamide-only group 13.55 (7.07)
Safinamide + antidepressants group 13.61 (6.38)
III Mean (SD) Complete cohort 22.91 (8.68)
Safinamide-only group 22.47 (9.90)
Safinamide + antidepressants group 23.30 (7.57)
IV Mean (SD) Complete cohort 3.51 (2.83)
Safinamide-only group 2.61 (2.52)
Safinamide + antidepressants group 4.30 (2.87)
HAMD-17 Mean (SD) Complete cohort 19.49 (4.03)
Safinamide-only group 18.39 (3.58)
Safinamide + antidepressants group 20.43 (4.20)
LEDD (mg) Mean (SD) Complete cohort 810.26 (368.45)
Safinamide-only group 681.25 (218.15)
Safinamide + antidepressants group 921.68 (432.86)
UPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.
brainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.
Antidepressant Drug Range of Doses (mg/day) n (%)
DULOXETINE 30–120 11 (25.0%)
ESCITALOPRAM 5–15 7 (15.9%)
MIRTAZAPINE 15–30 5 (11.4%)
SERTRALINE 50–100 5 (11.4%)
VENLAFAXINE 75–150 5 (11.4%)
TRAZODONE 50–100 4 (9.1%)
AMITRIPTILINE 25 1 (2.3%)
CLORIMIPRAMINE 25 1 (2.3%)
BUPROPION 150 1 (2.3%)
CITALOPRAM 20 1 (2.3%)
PAROXETINE + AMITRIPTILINE 10 + 25 1 (2.3%)
VENLAFAXINE + MIRTAZAPINE 75 + 15 1 (2.3%)
VORTIOXETINE 10 1 (2.3%)
brainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.
Baseline
Mean (SD) 1 Month
Mean Difference from Baseline (SD) p-Value 3 Months
Mean Difference from Baseline (SD) p-Value
HAMD-17 Complete cohort 19.49 (4.03)
n = 82 −6 (5.10)
n = 78 p < 0.0001 −7.27 (5.48)
n = 82 p < 0.0001
Safinamide 50 mg 18.50 (2.69)
n = 22 −3.32 (4.54)
n = 22 p = 0.0003 −4.73 (4.49)
n = 22 p < 0.0001
Safinamide 100 mg 19.85 (4.39)
n = 60 −7.03 (5.19)
n = 56 p < 0.0001 −8.02 (5.73)
n = 60 p < 0.0001
UPDRS I Complete cohort 4.56 (1.82)
n = 82 −1.32 (1.99)
n = 78 p < 0.0001 −1.5 (2.03)
n = 82 p < 0.0001
Safinamide 50 mg 4.59 (1.47)
n = 22 −0.64 (1.91)
n = 22 p = 0.0157 −0.91 (1.76)
n = 22 p = 0.0045
Safinamide 100 mg 4.55 (1.94)
n = 60 −1.59 (1.97)
n = 56 p < 0.0001 −1.72 (2.08)
n = 60 p < 0.0001
UPDRS II Complete cohort 13.59 (6.67)
n = 82 −2.51 (6.30)
n = 78 p < 0.0001 −2.47 (6.11)
n = 82 p < 0.0001
Safinamide 50 mg 11.50 (5.20)
n = 22 −0.36 (5.44)
n = 22 p = 0.4064 −0.23 (5.23)
n = 22 p = 0.4966
Safinamide 100 mg 14.35 (7.02)
n = 60 −3.30 (6.65)
n = 56 p < 0.0001 −3.28 (6.45)
n = 60 p < 0.0001
UPDRS III Complete cohort 22.91 (8.68)
n = 82 −3.58 (8.56)
n = 78 p < 0.0001 −4.03 (8.95)
n = 82 p < 0.0001
Safinamide 50 mg 22.00 (8.12)
n = 22 −0.41 (8.88)
n = 22 p = 0.7722 +0.50 (9.42)
n = 22 p = 0.6723
Safinamide 100 mg 23.25 (8.92)
n = 60 −4.8 (8.34)
n= 56 p < 0.0001 −5.70 (8.47)
n = 60 p < 0.0001
UPDRS IV Complete cohort 3.51 (2.83)
n = 82 −0.61 (2.61)
n = 78 p = 0.0003 −0.8 (2.53)
n = 82 p < 0.0001
Safinamide 50 mg 4.64 (2.59)
n = 22 −0.32 (2.38)
n = 22 p = 0.1839 −0.28 (2.50)
n = 22 p = 0.2482
Safinamide 100 mg 3.10 (2.82)
n = 60 −0.76 (2.50)
n = 56 p = 0.0007 −1.00 (2.28)
n = 60 p < 0.0001
HAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.
brainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.
1 Month 3 Months
Safinamide + Antidepressants Group
n = 42 Safinamide-only Group
n = 36 p-Value Safinamide + Antidepressants Group
n = 44 Safinamide-only Group
n = 38 p-Value
Major symptoms Confusion n (%) 2 (2.6%) 0 (0%) p = 0.564 1 (1.2%) 0 (0%) p = 1.251
Emotional lability 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 1 (1.2%) p = 0.627
Fever 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Sweating 3 (3.8%) 1 (1.3%) p = 0.627 3 (3.7%) 0 (0%) p = 0.266
Myoclonus 0 (0%) 0 (0%) - 2 (2.4%) 0 (0%) p = 0.565
Minor symptoms Agitation n (%) 2 (2.6%) 1 (1.3%) p = 1.021 1 (1.2%) 0 (0%) p = 1.251
Sleep disorders 13 (16.7%) 4 (5.1%) p = 0.053 13 (15.9%) 4 (4.9%) p = 0.054
Nervousness 15 (19.2%) 4 (5.1%) p = 0.017 13 (15.9%) 5 (6.1%) p = 0.108
Tachycardia 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 0 (0%) p = 0.266
Hyperventilation 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Dyspnea 1 (1.3%) 2 (2.6%) p = 0.642 2 (2.4%) 3 (3.7%) p = 0.666
Diarrhea 0 (0%) 1 (1.3%) p = 0.897 1 (1.2%) 0 (0%) p = 1.251
Hypertension 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Hypotension 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Ataxia 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Data were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.
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What was the outcome of reaction 'Diarrhoea'? | Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.
BACKGROUND
We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).
METHODS
We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.
RESULTS
n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.
CONCLUSIONS
Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
1. Introduction
Safinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].
Depression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.
Concerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.
The aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.
2. Materials and Methods
2.1. Study Design and Population
This was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.
The sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.
The primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.
As for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.
To test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].
Levodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].
2.2. Statistical Analyzsis
The demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.
3. Results
We enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.
The doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.
3.1. Effect of Safinamide on Depression in PD Patients
The primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).
3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice
In the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).
3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events
The relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.
Finally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.
4. Discussion
Safinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.
Although robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.
Based on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].
We found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].
We must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.
5. Conclusions
Safinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.
Acknowledgments
This is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.
Author Contributions
Conceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.
Funding
This study was funded by Zambon.
Institutional Review Board Statement
Ethical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.
Informed Consent Statement
Informed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Esteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.
Figure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.
brainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).
n n (%) Complete cohort 82
Safinamide-only group 38 (46.3%)
Safinamide + antidepressants group 44 (53.7%)
Age (years) Mean (SD) [range] Complete cohort 68.33 (11.41) [41–90]
Ssafinamide-only group 70.13 (9.83) [41–87]
Safinamide + antidepressants group 66.77 (12.51) [42–90]
Gender (male/female) n (%)/n (%) Complete cohort 37 (45.1%)/45 (54.9%)
Safinamide-only group 21 (55.3%)/17 (44.7%)
Safinamide + antidepressants group 16 (36.4%)/28 (63.6%)
Disease duration (years) Mean (SD) Complete cohort 8.67 (8.55)
Safinamide-only group 7.84 (9.65)
Safinamide + antidepressants group 9.39 (7.51)
UPDRS
I Mean (SD) Complete cohort 4.56 (1.82)
Safinamide-only group 3.82 (1.90)
Safinamide + antidepressants group 5.20 (1.49)
II Mean (SD) Complete cohort 13.59 (6.67)
Safinamide-only group 13.55 (7.07)
Safinamide + antidepressants group 13.61 (6.38)
III Mean (SD) Complete cohort 22.91 (8.68)
Safinamide-only group 22.47 (9.90)
Safinamide + antidepressants group 23.30 (7.57)
IV Mean (SD) Complete cohort 3.51 (2.83)
Safinamide-only group 2.61 (2.52)
Safinamide + antidepressants group 4.30 (2.87)
HAMD-17 Mean (SD) Complete cohort 19.49 (4.03)
Safinamide-only group 18.39 (3.58)
Safinamide + antidepressants group 20.43 (4.20)
LEDD (mg) Mean (SD) Complete cohort 810.26 (368.45)
Safinamide-only group 681.25 (218.15)
Safinamide + antidepressants group 921.68 (432.86)
UPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.
brainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.
Antidepressant Drug Range of Doses (mg/day) n (%)
DULOXETINE 30–120 11 (25.0%)
ESCITALOPRAM 5–15 7 (15.9%)
MIRTAZAPINE 15–30 5 (11.4%)
SERTRALINE 50–100 5 (11.4%)
VENLAFAXINE 75–150 5 (11.4%)
TRAZODONE 50–100 4 (9.1%)
AMITRIPTILINE 25 1 (2.3%)
CLORIMIPRAMINE 25 1 (2.3%)
BUPROPION 150 1 (2.3%)
CITALOPRAM 20 1 (2.3%)
PAROXETINE + AMITRIPTILINE 10 + 25 1 (2.3%)
VENLAFAXINE + MIRTAZAPINE 75 + 15 1 (2.3%)
VORTIOXETINE 10 1 (2.3%)
brainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.
Baseline
Mean (SD) 1 Month
Mean Difference from Baseline (SD) p-Value 3 Months
Mean Difference from Baseline (SD) p-Value
HAMD-17 Complete cohort 19.49 (4.03)
n = 82 −6 (5.10)
n = 78 p < 0.0001 −7.27 (5.48)
n = 82 p < 0.0001
Safinamide 50 mg 18.50 (2.69)
n = 22 −3.32 (4.54)
n = 22 p = 0.0003 −4.73 (4.49)
n = 22 p < 0.0001
Safinamide 100 mg 19.85 (4.39)
n = 60 −7.03 (5.19)
n = 56 p < 0.0001 −8.02 (5.73)
n = 60 p < 0.0001
UPDRS I Complete cohort 4.56 (1.82)
n = 82 −1.32 (1.99)
n = 78 p < 0.0001 −1.5 (2.03)
n = 82 p < 0.0001
Safinamide 50 mg 4.59 (1.47)
n = 22 −0.64 (1.91)
n = 22 p = 0.0157 −0.91 (1.76)
n = 22 p = 0.0045
Safinamide 100 mg 4.55 (1.94)
n = 60 −1.59 (1.97)
n = 56 p < 0.0001 −1.72 (2.08)
n = 60 p < 0.0001
UPDRS II Complete cohort 13.59 (6.67)
n = 82 −2.51 (6.30)
n = 78 p < 0.0001 −2.47 (6.11)
n = 82 p < 0.0001
Safinamide 50 mg 11.50 (5.20)
n = 22 −0.36 (5.44)
n = 22 p = 0.4064 −0.23 (5.23)
n = 22 p = 0.4966
Safinamide 100 mg 14.35 (7.02)
n = 60 −3.30 (6.65)
n = 56 p < 0.0001 −3.28 (6.45)
n = 60 p < 0.0001
UPDRS III Complete cohort 22.91 (8.68)
n = 82 −3.58 (8.56)
n = 78 p < 0.0001 −4.03 (8.95)
n = 82 p < 0.0001
Safinamide 50 mg 22.00 (8.12)
n = 22 −0.41 (8.88)
n = 22 p = 0.7722 +0.50 (9.42)
n = 22 p = 0.6723
Safinamide 100 mg 23.25 (8.92)
n = 60 −4.8 (8.34)
n= 56 p < 0.0001 −5.70 (8.47)
n = 60 p < 0.0001
UPDRS IV Complete cohort 3.51 (2.83)
n = 82 −0.61 (2.61)
n = 78 p = 0.0003 −0.8 (2.53)
n = 82 p < 0.0001
Safinamide 50 mg 4.64 (2.59)
n = 22 −0.32 (2.38)
n = 22 p = 0.1839 −0.28 (2.50)
n = 22 p = 0.2482
Safinamide 100 mg 3.10 (2.82)
n = 60 −0.76 (2.50)
n = 56 p = 0.0007 −1.00 (2.28)
n = 60 p < 0.0001
HAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.
brainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.
1 Month 3 Months
Safinamide + Antidepressants Group
n = 42 Safinamide-only Group
n = 36 p-Value Safinamide + Antidepressants Group
n = 44 Safinamide-only Group
n = 38 p-Value
Major symptoms Confusion n (%) 2 (2.6%) 0 (0%) p = 0.564 1 (1.2%) 0 (0%) p = 1.251
Emotional lability 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 1 (1.2%) p = 0.627
Fever 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Sweating 3 (3.8%) 1 (1.3%) p = 0.627 3 (3.7%) 0 (0%) p = 0.266
Myoclonus 0 (0%) 0 (0%) - 2 (2.4%) 0 (0%) p = 0.565
Minor symptoms Agitation n (%) 2 (2.6%) 1 (1.3%) p = 1.021 1 (1.2%) 0 (0%) p = 1.251
Sleep disorders 13 (16.7%) 4 (5.1%) p = 0.053 13 (15.9%) 4 (4.9%) p = 0.054
Nervousness 15 (19.2%) 4 (5.1%) p = 0.017 13 (15.9%) 5 (6.1%) p = 0.108
Tachycardia 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 0 (0%) p = 0.266
Hyperventilation 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Dyspnea 1 (1.3%) 2 (2.6%) p = 0.642 2 (2.4%) 3 (3.7%) p = 0.666
Diarrhea 0 (0%) 1 (1.3%) p = 0.897 1 (1.2%) 0 (0%) p = 1.251
Hypertension 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Hypotension 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Ataxia 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Data were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.
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What was the outcome of reaction 'Labelled drug-drug interaction issue'? | Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.
BACKGROUND
We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).
METHODS
We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.
RESULTS
n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.
CONCLUSIONS
Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
1. Introduction
Safinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].
Depression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.
Concerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.
The aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.
2. Materials and Methods
2.1. Study Design and Population
This was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.
The sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.
The primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.
As for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.
To test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].
Levodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].
2.2. Statistical Analyzsis
The demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.
3. Results
We enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.
The doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.
3.1. Effect of Safinamide on Depression in PD Patients
The primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).
3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice
In the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).
3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events
The relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.
Finally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.
4. Discussion
Safinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.
Although robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.
Based on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].
We found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].
We must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.
5. Conclusions
Safinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.
Acknowledgments
This is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.
Author Contributions
Conceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.
Funding
This study was funded by Zambon.
Institutional Review Board Statement
Ethical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.
Informed Consent Statement
Informed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Esteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.
Figure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.
brainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).
n n (%) Complete cohort 82
Safinamide-only group 38 (46.3%)
Safinamide + antidepressants group 44 (53.7%)
Age (years) Mean (SD) [range] Complete cohort 68.33 (11.41) [41–90]
Ssafinamide-only group 70.13 (9.83) [41–87]
Safinamide + antidepressants group 66.77 (12.51) [42–90]
Gender (male/female) n (%)/n (%) Complete cohort 37 (45.1%)/45 (54.9%)
Safinamide-only group 21 (55.3%)/17 (44.7%)
Safinamide + antidepressants group 16 (36.4%)/28 (63.6%)
Disease duration (years) Mean (SD) Complete cohort 8.67 (8.55)
Safinamide-only group 7.84 (9.65)
Safinamide + antidepressants group 9.39 (7.51)
UPDRS
I Mean (SD) Complete cohort 4.56 (1.82)
Safinamide-only group 3.82 (1.90)
Safinamide + antidepressants group 5.20 (1.49)
II Mean (SD) Complete cohort 13.59 (6.67)
Safinamide-only group 13.55 (7.07)
Safinamide + antidepressants group 13.61 (6.38)
III Mean (SD) Complete cohort 22.91 (8.68)
Safinamide-only group 22.47 (9.90)
Safinamide + antidepressants group 23.30 (7.57)
IV Mean (SD) Complete cohort 3.51 (2.83)
Safinamide-only group 2.61 (2.52)
Safinamide + antidepressants group 4.30 (2.87)
HAMD-17 Mean (SD) Complete cohort 19.49 (4.03)
Safinamide-only group 18.39 (3.58)
Safinamide + antidepressants group 20.43 (4.20)
LEDD (mg) Mean (SD) Complete cohort 810.26 (368.45)
Safinamide-only group 681.25 (218.15)
Safinamide + antidepressants group 921.68 (432.86)
UPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.
brainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.
Antidepressant Drug Range of Doses (mg/day) n (%)
DULOXETINE 30–120 11 (25.0%)
ESCITALOPRAM 5–15 7 (15.9%)
MIRTAZAPINE 15–30 5 (11.4%)
SERTRALINE 50–100 5 (11.4%)
VENLAFAXINE 75–150 5 (11.4%)
TRAZODONE 50–100 4 (9.1%)
AMITRIPTILINE 25 1 (2.3%)
CLORIMIPRAMINE 25 1 (2.3%)
BUPROPION 150 1 (2.3%)
CITALOPRAM 20 1 (2.3%)
PAROXETINE + AMITRIPTILINE 10 + 25 1 (2.3%)
VENLAFAXINE + MIRTAZAPINE 75 + 15 1 (2.3%)
VORTIOXETINE 10 1 (2.3%)
brainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.
Baseline
Mean (SD) 1 Month
Mean Difference from Baseline (SD) p-Value 3 Months
Mean Difference from Baseline (SD) p-Value
HAMD-17 Complete cohort 19.49 (4.03)
n = 82 −6 (5.10)
n = 78 p < 0.0001 −7.27 (5.48)
n = 82 p < 0.0001
Safinamide 50 mg 18.50 (2.69)
n = 22 −3.32 (4.54)
n = 22 p = 0.0003 −4.73 (4.49)
n = 22 p < 0.0001
Safinamide 100 mg 19.85 (4.39)
n = 60 −7.03 (5.19)
n = 56 p < 0.0001 −8.02 (5.73)
n = 60 p < 0.0001
UPDRS I Complete cohort 4.56 (1.82)
n = 82 −1.32 (1.99)
n = 78 p < 0.0001 −1.5 (2.03)
n = 82 p < 0.0001
Safinamide 50 mg 4.59 (1.47)
n = 22 −0.64 (1.91)
n = 22 p = 0.0157 −0.91 (1.76)
n = 22 p = 0.0045
Safinamide 100 mg 4.55 (1.94)
n = 60 −1.59 (1.97)
n = 56 p < 0.0001 −1.72 (2.08)
n = 60 p < 0.0001
UPDRS II Complete cohort 13.59 (6.67)
n = 82 −2.51 (6.30)
n = 78 p < 0.0001 −2.47 (6.11)
n = 82 p < 0.0001
Safinamide 50 mg 11.50 (5.20)
n = 22 −0.36 (5.44)
n = 22 p = 0.4064 −0.23 (5.23)
n = 22 p = 0.4966
Safinamide 100 mg 14.35 (7.02)
n = 60 −3.30 (6.65)
n = 56 p < 0.0001 −3.28 (6.45)
n = 60 p < 0.0001
UPDRS III Complete cohort 22.91 (8.68)
n = 82 −3.58 (8.56)
n = 78 p < 0.0001 −4.03 (8.95)
n = 82 p < 0.0001
Safinamide 50 mg 22.00 (8.12)
n = 22 −0.41 (8.88)
n = 22 p = 0.7722 +0.50 (9.42)
n = 22 p = 0.6723
Safinamide 100 mg 23.25 (8.92)
n = 60 −4.8 (8.34)
n= 56 p < 0.0001 −5.70 (8.47)
n = 60 p < 0.0001
UPDRS IV Complete cohort 3.51 (2.83)
n = 82 −0.61 (2.61)
n = 78 p = 0.0003 −0.8 (2.53)
n = 82 p < 0.0001
Safinamide 50 mg 4.64 (2.59)
n = 22 −0.32 (2.38)
n = 22 p = 0.1839 −0.28 (2.50)
n = 22 p = 0.2482
Safinamide 100 mg 3.10 (2.82)
n = 60 −0.76 (2.50)
n = 56 p = 0.0007 −1.00 (2.28)
n = 60 p < 0.0001
HAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.
brainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.
1 Month 3 Months
Safinamide + Antidepressants Group
n = 42 Safinamide-only Group
n = 36 p-Value Safinamide + Antidepressants Group
n = 44 Safinamide-only Group
n = 38 p-Value
Major symptoms Confusion n (%) 2 (2.6%) 0 (0%) p = 0.564 1 (1.2%) 0 (0%) p = 1.251
Emotional lability 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 1 (1.2%) p = 0.627
Fever 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Sweating 3 (3.8%) 1 (1.3%) p = 0.627 3 (3.7%) 0 (0%) p = 0.266
Myoclonus 0 (0%) 0 (0%) - 2 (2.4%) 0 (0%) p = 0.565
Minor symptoms Agitation n (%) 2 (2.6%) 1 (1.3%) p = 1.021 1 (1.2%) 0 (0%) p = 1.251
Sleep disorders 13 (16.7%) 4 (5.1%) p = 0.053 13 (15.9%) 4 (4.9%) p = 0.054
Nervousness 15 (19.2%) 4 (5.1%) p = 0.017 13 (15.9%) 5 (6.1%) p = 0.108
Tachycardia 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 0 (0%) p = 0.266
Hyperventilation 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Dyspnea 1 (1.3%) 2 (2.6%) p = 0.642 2 (2.4%) 3 (3.7%) p = 0.666
Diarrhea 0 (0%) 1 (1.3%) p = 0.897 1 (1.2%) 0 (0%) p = 1.251
Hypertension 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Hypotension 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Ataxia 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Data were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.
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What was the outcome of reaction 'Myoclonus'? | Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.
BACKGROUND
We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).
METHODS
We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.
RESULTS
n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.
CONCLUSIONS
Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
1. Introduction
Safinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].
Depression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.
Concerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.
The aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.
2. Materials and Methods
2.1. Study Design and Population
This was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.
The sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.
The primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.
As for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.
To test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].
Levodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].
2.2. Statistical Analyzsis
The demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.
3. Results
We enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.
The doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.
3.1. Effect of Safinamide on Depression in PD Patients
The primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).
3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice
In the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).
3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events
The relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.
Finally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.
4. Discussion
Safinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.
Although robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.
Based on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].
We found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].
We must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.
5. Conclusions
Safinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.
Acknowledgments
This is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.
Author Contributions
Conceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.
Funding
This study was funded by Zambon.
Institutional Review Board Statement
Ethical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.
Informed Consent Statement
Informed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Esteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.
Figure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.
brainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).
n n (%) Complete cohort 82
Safinamide-only group 38 (46.3%)
Safinamide + antidepressants group 44 (53.7%)
Age (years) Mean (SD) [range] Complete cohort 68.33 (11.41) [41–90]
Ssafinamide-only group 70.13 (9.83) [41–87]
Safinamide + antidepressants group 66.77 (12.51) [42–90]
Gender (male/female) n (%)/n (%) Complete cohort 37 (45.1%)/45 (54.9%)
Safinamide-only group 21 (55.3%)/17 (44.7%)
Safinamide + antidepressants group 16 (36.4%)/28 (63.6%)
Disease duration (years) Mean (SD) Complete cohort 8.67 (8.55)
Safinamide-only group 7.84 (9.65)
Safinamide + antidepressants group 9.39 (7.51)
UPDRS
I Mean (SD) Complete cohort 4.56 (1.82)
Safinamide-only group 3.82 (1.90)
Safinamide + antidepressants group 5.20 (1.49)
II Mean (SD) Complete cohort 13.59 (6.67)
Safinamide-only group 13.55 (7.07)
Safinamide + antidepressants group 13.61 (6.38)
III Mean (SD) Complete cohort 22.91 (8.68)
Safinamide-only group 22.47 (9.90)
Safinamide + antidepressants group 23.30 (7.57)
IV Mean (SD) Complete cohort 3.51 (2.83)
Safinamide-only group 2.61 (2.52)
Safinamide + antidepressants group 4.30 (2.87)
HAMD-17 Mean (SD) Complete cohort 19.49 (4.03)
Safinamide-only group 18.39 (3.58)
Safinamide + antidepressants group 20.43 (4.20)
LEDD (mg) Mean (SD) Complete cohort 810.26 (368.45)
Safinamide-only group 681.25 (218.15)
Safinamide + antidepressants group 921.68 (432.86)
UPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.
brainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.
Antidepressant Drug Range of Doses (mg/day) n (%)
DULOXETINE 30–120 11 (25.0%)
ESCITALOPRAM 5–15 7 (15.9%)
MIRTAZAPINE 15–30 5 (11.4%)
SERTRALINE 50–100 5 (11.4%)
VENLAFAXINE 75–150 5 (11.4%)
TRAZODONE 50–100 4 (9.1%)
AMITRIPTILINE 25 1 (2.3%)
CLORIMIPRAMINE 25 1 (2.3%)
BUPROPION 150 1 (2.3%)
CITALOPRAM 20 1 (2.3%)
PAROXETINE + AMITRIPTILINE 10 + 25 1 (2.3%)
VENLAFAXINE + MIRTAZAPINE 75 + 15 1 (2.3%)
VORTIOXETINE 10 1 (2.3%)
brainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.
Baseline
Mean (SD) 1 Month
Mean Difference from Baseline (SD) p-Value 3 Months
Mean Difference from Baseline (SD) p-Value
HAMD-17 Complete cohort 19.49 (4.03)
n = 82 −6 (5.10)
n = 78 p < 0.0001 −7.27 (5.48)
n = 82 p < 0.0001
Safinamide 50 mg 18.50 (2.69)
n = 22 −3.32 (4.54)
n = 22 p = 0.0003 −4.73 (4.49)
n = 22 p < 0.0001
Safinamide 100 mg 19.85 (4.39)
n = 60 −7.03 (5.19)
n = 56 p < 0.0001 −8.02 (5.73)
n = 60 p < 0.0001
UPDRS I Complete cohort 4.56 (1.82)
n = 82 −1.32 (1.99)
n = 78 p < 0.0001 −1.5 (2.03)
n = 82 p < 0.0001
Safinamide 50 mg 4.59 (1.47)
n = 22 −0.64 (1.91)
n = 22 p = 0.0157 −0.91 (1.76)
n = 22 p = 0.0045
Safinamide 100 mg 4.55 (1.94)
n = 60 −1.59 (1.97)
n = 56 p < 0.0001 −1.72 (2.08)
n = 60 p < 0.0001
UPDRS II Complete cohort 13.59 (6.67)
n = 82 −2.51 (6.30)
n = 78 p < 0.0001 −2.47 (6.11)
n = 82 p < 0.0001
Safinamide 50 mg 11.50 (5.20)
n = 22 −0.36 (5.44)
n = 22 p = 0.4064 −0.23 (5.23)
n = 22 p = 0.4966
Safinamide 100 mg 14.35 (7.02)
n = 60 −3.30 (6.65)
n = 56 p < 0.0001 −3.28 (6.45)
n = 60 p < 0.0001
UPDRS III Complete cohort 22.91 (8.68)
n = 82 −3.58 (8.56)
n = 78 p < 0.0001 −4.03 (8.95)
n = 82 p < 0.0001
Safinamide 50 mg 22.00 (8.12)
n = 22 −0.41 (8.88)
n = 22 p = 0.7722 +0.50 (9.42)
n = 22 p = 0.6723
Safinamide 100 mg 23.25 (8.92)
n = 60 −4.8 (8.34)
n= 56 p < 0.0001 −5.70 (8.47)
n = 60 p < 0.0001
UPDRS IV Complete cohort 3.51 (2.83)
n = 82 −0.61 (2.61)
n = 78 p = 0.0003 −0.8 (2.53)
n = 82 p < 0.0001
Safinamide 50 mg 4.64 (2.59)
n = 22 −0.32 (2.38)
n = 22 p = 0.1839 −0.28 (2.50)
n = 22 p = 0.2482
Safinamide 100 mg 3.10 (2.82)
n = 60 −0.76 (2.50)
n = 56 p = 0.0007 −1.00 (2.28)
n = 60 p < 0.0001
HAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.
brainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.
1 Month 3 Months
Safinamide + Antidepressants Group
n = 42 Safinamide-only Group
n = 36 p-Value Safinamide + Antidepressants Group
n = 44 Safinamide-only Group
n = 38 p-Value
Major symptoms Confusion n (%) 2 (2.6%) 0 (0%) p = 0.564 1 (1.2%) 0 (0%) p = 1.251
Emotional lability 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 1 (1.2%) p = 0.627
Fever 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Sweating 3 (3.8%) 1 (1.3%) p = 0.627 3 (3.7%) 0 (0%) p = 0.266
Myoclonus 0 (0%) 0 (0%) - 2 (2.4%) 0 (0%) p = 0.565
Minor symptoms Agitation n (%) 2 (2.6%) 1 (1.3%) p = 1.021 1 (1.2%) 0 (0%) p = 1.251
Sleep disorders 13 (16.7%) 4 (5.1%) p = 0.053 13 (15.9%) 4 (4.9%) p = 0.054
Nervousness 15 (19.2%) 4 (5.1%) p = 0.017 13 (15.9%) 5 (6.1%) p = 0.108
Tachycardia 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 0 (0%) p = 0.266
Hyperventilation 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Dyspnea 1 (1.3%) 2 (2.6%) p = 0.642 2 (2.4%) 3 (3.7%) p = 0.666
Diarrhea 0 (0%) 1 (1.3%) p = 0.897 1 (1.2%) 0 (0%) p = 1.251
Hypertension 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Hypotension 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Ataxia 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Data were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.
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What was the outcome of reaction 'Nervousness'? | Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.
BACKGROUND
We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).
METHODS
We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.
RESULTS
n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.
CONCLUSIONS
Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
1. Introduction
Safinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].
Depression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.
Concerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.
The aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.
2. Materials and Methods
2.1. Study Design and Population
This was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.
The sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.
The primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.
As for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.
To test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].
Levodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].
2.2. Statistical Analyzsis
The demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.
3. Results
We enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.
The doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.
3.1. Effect of Safinamide on Depression in PD Patients
The primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).
3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice
In the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).
3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events
The relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.
Finally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.
4. Discussion
Safinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.
Although robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.
Based on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].
We found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].
We must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.
5. Conclusions
Safinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.
Acknowledgments
This is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.
Author Contributions
Conceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.
Funding
This study was funded by Zambon.
Institutional Review Board Statement
Ethical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.
Informed Consent Statement
Informed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Esteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.
Figure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.
brainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).
n n (%) Complete cohort 82
Safinamide-only group 38 (46.3%)
Safinamide + antidepressants group 44 (53.7%)
Age (years) Mean (SD) [range] Complete cohort 68.33 (11.41) [41–90]
Ssafinamide-only group 70.13 (9.83) [41–87]
Safinamide + antidepressants group 66.77 (12.51) [42–90]
Gender (male/female) n (%)/n (%) Complete cohort 37 (45.1%)/45 (54.9%)
Safinamide-only group 21 (55.3%)/17 (44.7%)
Safinamide + antidepressants group 16 (36.4%)/28 (63.6%)
Disease duration (years) Mean (SD) Complete cohort 8.67 (8.55)
Safinamide-only group 7.84 (9.65)
Safinamide + antidepressants group 9.39 (7.51)
UPDRS
I Mean (SD) Complete cohort 4.56 (1.82)
Safinamide-only group 3.82 (1.90)
Safinamide + antidepressants group 5.20 (1.49)
II Mean (SD) Complete cohort 13.59 (6.67)
Safinamide-only group 13.55 (7.07)
Safinamide + antidepressants group 13.61 (6.38)
III Mean (SD) Complete cohort 22.91 (8.68)
Safinamide-only group 22.47 (9.90)
Safinamide + antidepressants group 23.30 (7.57)
IV Mean (SD) Complete cohort 3.51 (2.83)
Safinamide-only group 2.61 (2.52)
Safinamide + antidepressants group 4.30 (2.87)
HAMD-17 Mean (SD) Complete cohort 19.49 (4.03)
Safinamide-only group 18.39 (3.58)
Safinamide + antidepressants group 20.43 (4.20)
LEDD (mg) Mean (SD) Complete cohort 810.26 (368.45)
Safinamide-only group 681.25 (218.15)
Safinamide + antidepressants group 921.68 (432.86)
UPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.
brainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.
Antidepressant Drug Range of Doses (mg/day) n (%)
DULOXETINE 30–120 11 (25.0%)
ESCITALOPRAM 5–15 7 (15.9%)
MIRTAZAPINE 15–30 5 (11.4%)
SERTRALINE 50–100 5 (11.4%)
VENLAFAXINE 75–150 5 (11.4%)
TRAZODONE 50–100 4 (9.1%)
AMITRIPTILINE 25 1 (2.3%)
CLORIMIPRAMINE 25 1 (2.3%)
BUPROPION 150 1 (2.3%)
CITALOPRAM 20 1 (2.3%)
PAROXETINE + AMITRIPTILINE 10 + 25 1 (2.3%)
VENLAFAXINE + MIRTAZAPINE 75 + 15 1 (2.3%)
VORTIOXETINE 10 1 (2.3%)
brainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.
Baseline
Mean (SD) 1 Month
Mean Difference from Baseline (SD) p-Value 3 Months
Mean Difference from Baseline (SD) p-Value
HAMD-17 Complete cohort 19.49 (4.03)
n = 82 −6 (5.10)
n = 78 p < 0.0001 −7.27 (5.48)
n = 82 p < 0.0001
Safinamide 50 mg 18.50 (2.69)
n = 22 −3.32 (4.54)
n = 22 p = 0.0003 −4.73 (4.49)
n = 22 p < 0.0001
Safinamide 100 mg 19.85 (4.39)
n = 60 −7.03 (5.19)
n = 56 p < 0.0001 −8.02 (5.73)
n = 60 p < 0.0001
UPDRS I Complete cohort 4.56 (1.82)
n = 82 −1.32 (1.99)
n = 78 p < 0.0001 −1.5 (2.03)
n = 82 p < 0.0001
Safinamide 50 mg 4.59 (1.47)
n = 22 −0.64 (1.91)
n = 22 p = 0.0157 −0.91 (1.76)
n = 22 p = 0.0045
Safinamide 100 mg 4.55 (1.94)
n = 60 −1.59 (1.97)
n = 56 p < 0.0001 −1.72 (2.08)
n = 60 p < 0.0001
UPDRS II Complete cohort 13.59 (6.67)
n = 82 −2.51 (6.30)
n = 78 p < 0.0001 −2.47 (6.11)
n = 82 p < 0.0001
Safinamide 50 mg 11.50 (5.20)
n = 22 −0.36 (5.44)
n = 22 p = 0.4064 −0.23 (5.23)
n = 22 p = 0.4966
Safinamide 100 mg 14.35 (7.02)
n = 60 −3.30 (6.65)
n = 56 p < 0.0001 −3.28 (6.45)
n = 60 p < 0.0001
UPDRS III Complete cohort 22.91 (8.68)
n = 82 −3.58 (8.56)
n = 78 p < 0.0001 −4.03 (8.95)
n = 82 p < 0.0001
Safinamide 50 mg 22.00 (8.12)
n = 22 −0.41 (8.88)
n = 22 p = 0.7722 +0.50 (9.42)
n = 22 p = 0.6723
Safinamide 100 mg 23.25 (8.92)
n = 60 −4.8 (8.34)
n= 56 p < 0.0001 −5.70 (8.47)
n = 60 p < 0.0001
UPDRS IV Complete cohort 3.51 (2.83)
n = 82 −0.61 (2.61)
n = 78 p = 0.0003 −0.8 (2.53)
n = 82 p < 0.0001
Safinamide 50 mg 4.64 (2.59)
n = 22 −0.32 (2.38)
n = 22 p = 0.1839 −0.28 (2.50)
n = 22 p = 0.2482
Safinamide 100 mg 3.10 (2.82)
n = 60 −0.76 (2.50)
n = 56 p = 0.0007 −1.00 (2.28)
n = 60 p < 0.0001
HAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.
brainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.
1 Month 3 Months
Safinamide + Antidepressants Group
n = 42 Safinamide-only Group
n = 36 p-Value Safinamide + Antidepressants Group
n = 44 Safinamide-only Group
n = 38 p-Value
Major symptoms Confusion n (%) 2 (2.6%) 0 (0%) p = 0.564 1 (1.2%) 0 (0%) p = 1.251
Emotional lability 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 1 (1.2%) p = 0.627
Fever 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Sweating 3 (3.8%) 1 (1.3%) p = 0.627 3 (3.7%) 0 (0%) p = 0.266
Myoclonus 0 (0%) 0 (0%) - 2 (2.4%) 0 (0%) p = 0.565
Minor symptoms Agitation n (%) 2 (2.6%) 1 (1.3%) p = 1.021 1 (1.2%) 0 (0%) p = 1.251
Sleep disorders 13 (16.7%) 4 (5.1%) p = 0.053 13 (15.9%) 4 (4.9%) p = 0.054
Nervousness 15 (19.2%) 4 (5.1%) p = 0.017 13 (15.9%) 5 (6.1%) p = 0.108
Tachycardia 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 0 (0%) p = 0.266
Hyperventilation 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Dyspnea 1 (1.3%) 2 (2.6%) p = 0.642 2 (2.4%) 3 (3.7%) p = 0.666
Diarrhea 0 (0%) 1 (1.3%) p = 0.897 1 (1.2%) 0 (0%) p = 1.251
Hypertension 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Hypotension 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Ataxia 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Data were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.
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What was the outcome of reaction 'Serotonin syndrome'? | Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.
BACKGROUND
We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).
METHODS
We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.
RESULTS
n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.
CONCLUSIONS
Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
1. Introduction
Safinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].
Depression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.
Concerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.
The aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.
2. Materials and Methods
2.1. Study Design and Population
This was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.
The sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.
The primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.
As for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.
To test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].
Levodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].
2.2. Statistical Analyzsis
The demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.
3. Results
We enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.
The doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.
3.1. Effect of Safinamide on Depression in PD Patients
The primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).
3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice
In the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).
3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events
The relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.
Finally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.
4. Discussion
Safinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.
Although robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.
Based on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].
We found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].
We must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.
5. Conclusions
Safinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.
Acknowledgments
This is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.
Author Contributions
Conceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.
Funding
This study was funded by Zambon.
Institutional Review Board Statement
Ethical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.
Informed Consent Statement
Informed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Esteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.
Figure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.
brainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).
n n (%) Complete cohort 82
Safinamide-only group 38 (46.3%)
Safinamide + antidepressants group 44 (53.7%)
Age (years) Mean (SD) [range] Complete cohort 68.33 (11.41) [41–90]
Ssafinamide-only group 70.13 (9.83) [41–87]
Safinamide + antidepressants group 66.77 (12.51) [42–90]
Gender (male/female) n (%)/n (%) Complete cohort 37 (45.1%)/45 (54.9%)
Safinamide-only group 21 (55.3%)/17 (44.7%)
Safinamide + antidepressants group 16 (36.4%)/28 (63.6%)
Disease duration (years) Mean (SD) Complete cohort 8.67 (8.55)
Safinamide-only group 7.84 (9.65)
Safinamide + antidepressants group 9.39 (7.51)
UPDRS
I Mean (SD) Complete cohort 4.56 (1.82)
Safinamide-only group 3.82 (1.90)
Safinamide + antidepressants group 5.20 (1.49)
II Mean (SD) Complete cohort 13.59 (6.67)
Safinamide-only group 13.55 (7.07)
Safinamide + antidepressants group 13.61 (6.38)
III Mean (SD) Complete cohort 22.91 (8.68)
Safinamide-only group 22.47 (9.90)
Safinamide + antidepressants group 23.30 (7.57)
IV Mean (SD) Complete cohort 3.51 (2.83)
Safinamide-only group 2.61 (2.52)
Safinamide + antidepressants group 4.30 (2.87)
HAMD-17 Mean (SD) Complete cohort 19.49 (4.03)
Safinamide-only group 18.39 (3.58)
Safinamide + antidepressants group 20.43 (4.20)
LEDD (mg) Mean (SD) Complete cohort 810.26 (368.45)
Safinamide-only group 681.25 (218.15)
Safinamide + antidepressants group 921.68 (432.86)
UPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.
brainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.
Antidepressant Drug Range of Doses (mg/day) n (%)
DULOXETINE 30–120 11 (25.0%)
ESCITALOPRAM 5–15 7 (15.9%)
MIRTAZAPINE 15–30 5 (11.4%)
SERTRALINE 50–100 5 (11.4%)
VENLAFAXINE 75–150 5 (11.4%)
TRAZODONE 50–100 4 (9.1%)
AMITRIPTILINE 25 1 (2.3%)
CLORIMIPRAMINE 25 1 (2.3%)
BUPROPION 150 1 (2.3%)
CITALOPRAM 20 1 (2.3%)
PAROXETINE + AMITRIPTILINE 10 + 25 1 (2.3%)
VENLAFAXINE + MIRTAZAPINE 75 + 15 1 (2.3%)
VORTIOXETINE 10 1 (2.3%)
brainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.
Baseline
Mean (SD) 1 Month
Mean Difference from Baseline (SD) p-Value 3 Months
Mean Difference from Baseline (SD) p-Value
HAMD-17 Complete cohort 19.49 (4.03)
n = 82 −6 (5.10)
n = 78 p < 0.0001 −7.27 (5.48)
n = 82 p < 0.0001
Safinamide 50 mg 18.50 (2.69)
n = 22 −3.32 (4.54)
n = 22 p = 0.0003 −4.73 (4.49)
n = 22 p < 0.0001
Safinamide 100 mg 19.85 (4.39)
n = 60 −7.03 (5.19)
n = 56 p < 0.0001 −8.02 (5.73)
n = 60 p < 0.0001
UPDRS I Complete cohort 4.56 (1.82)
n = 82 −1.32 (1.99)
n = 78 p < 0.0001 −1.5 (2.03)
n = 82 p < 0.0001
Safinamide 50 mg 4.59 (1.47)
n = 22 −0.64 (1.91)
n = 22 p = 0.0157 −0.91 (1.76)
n = 22 p = 0.0045
Safinamide 100 mg 4.55 (1.94)
n = 60 −1.59 (1.97)
n = 56 p < 0.0001 −1.72 (2.08)
n = 60 p < 0.0001
UPDRS II Complete cohort 13.59 (6.67)
n = 82 −2.51 (6.30)
n = 78 p < 0.0001 −2.47 (6.11)
n = 82 p < 0.0001
Safinamide 50 mg 11.50 (5.20)
n = 22 −0.36 (5.44)
n = 22 p = 0.4064 −0.23 (5.23)
n = 22 p = 0.4966
Safinamide 100 mg 14.35 (7.02)
n = 60 −3.30 (6.65)
n = 56 p < 0.0001 −3.28 (6.45)
n = 60 p < 0.0001
UPDRS III Complete cohort 22.91 (8.68)
n = 82 −3.58 (8.56)
n = 78 p < 0.0001 −4.03 (8.95)
n = 82 p < 0.0001
Safinamide 50 mg 22.00 (8.12)
n = 22 −0.41 (8.88)
n = 22 p = 0.7722 +0.50 (9.42)
n = 22 p = 0.6723
Safinamide 100 mg 23.25 (8.92)
n = 60 −4.8 (8.34)
n= 56 p < 0.0001 −5.70 (8.47)
n = 60 p < 0.0001
UPDRS IV Complete cohort 3.51 (2.83)
n = 82 −0.61 (2.61)
n = 78 p = 0.0003 −0.8 (2.53)
n = 82 p < 0.0001
Safinamide 50 mg 4.64 (2.59)
n = 22 −0.32 (2.38)
n = 22 p = 0.1839 −0.28 (2.50)
n = 22 p = 0.2482
Safinamide 100 mg 3.10 (2.82)
n = 60 −0.76 (2.50)
n = 56 p = 0.0007 −1.00 (2.28)
n = 60 p < 0.0001
HAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.
brainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.
1 Month 3 Months
Safinamide + Antidepressants Group
n = 42 Safinamide-only Group
n = 36 p-Value Safinamide + Antidepressants Group
n = 44 Safinamide-only Group
n = 38 p-Value
Major symptoms Confusion n (%) 2 (2.6%) 0 (0%) p = 0.564 1 (1.2%) 0 (0%) p = 1.251
Emotional lability 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 1 (1.2%) p = 0.627
Fever 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Sweating 3 (3.8%) 1 (1.3%) p = 0.627 3 (3.7%) 0 (0%) p = 0.266
Myoclonus 0 (0%) 0 (0%) - 2 (2.4%) 0 (0%) p = 0.565
Minor symptoms Agitation n (%) 2 (2.6%) 1 (1.3%) p = 1.021 1 (1.2%) 0 (0%) p = 1.251
Sleep disorders 13 (16.7%) 4 (5.1%) p = 0.053 13 (15.9%) 4 (4.9%) p = 0.054
Nervousness 15 (19.2%) 4 (5.1%) p = 0.017 13 (15.9%) 5 (6.1%) p = 0.108
Tachycardia 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 0 (0%) p = 0.266
Hyperventilation 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Dyspnea 1 (1.3%) 2 (2.6%) p = 0.642 2 (2.4%) 3 (3.7%) p = 0.666
Diarrhea 0 (0%) 1 (1.3%) p = 0.897 1 (1.2%) 0 (0%) p = 1.251
Hypertension 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Hypotension 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Ataxia 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Data were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.
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What was the outcome of reaction 'Sleep disorder'? | Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.
BACKGROUND
We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).
METHODS
We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.
RESULTS
n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.
CONCLUSIONS
Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
1. Introduction
Safinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].
Depression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.
Concerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.
The aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.
2. Materials and Methods
2.1. Study Design and Population
This was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.
The sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.
The primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.
As for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.
To test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].
Levodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].
2.2. Statistical Analyzsis
The demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.
3. Results
We enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.
The doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.
3.1. Effect of Safinamide on Depression in PD Patients
The primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).
3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice
In the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).
3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events
The relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.
Finally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.
4. Discussion
Safinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.
Although robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.
Based on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].
We found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].
We must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.
5. Conclusions
Safinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.
Acknowledgments
This is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.
Author Contributions
Conceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.
Funding
This study was funded by Zambon.
Institutional Review Board Statement
Ethical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.
Informed Consent Statement
Informed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Esteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.
Figure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.
brainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).
n n (%) Complete cohort 82
Safinamide-only group 38 (46.3%)
Safinamide + antidepressants group 44 (53.7%)
Age (years) Mean (SD) [range] Complete cohort 68.33 (11.41) [41–90]
Ssafinamide-only group 70.13 (9.83) [41–87]
Safinamide + antidepressants group 66.77 (12.51) [42–90]
Gender (male/female) n (%)/n (%) Complete cohort 37 (45.1%)/45 (54.9%)
Safinamide-only group 21 (55.3%)/17 (44.7%)
Safinamide + antidepressants group 16 (36.4%)/28 (63.6%)
Disease duration (years) Mean (SD) Complete cohort 8.67 (8.55)
Safinamide-only group 7.84 (9.65)
Safinamide + antidepressants group 9.39 (7.51)
UPDRS
I Mean (SD) Complete cohort 4.56 (1.82)
Safinamide-only group 3.82 (1.90)
Safinamide + antidepressants group 5.20 (1.49)
II Mean (SD) Complete cohort 13.59 (6.67)
Safinamide-only group 13.55 (7.07)
Safinamide + antidepressants group 13.61 (6.38)
III Mean (SD) Complete cohort 22.91 (8.68)
Safinamide-only group 22.47 (9.90)
Safinamide + antidepressants group 23.30 (7.57)
IV Mean (SD) Complete cohort 3.51 (2.83)
Safinamide-only group 2.61 (2.52)
Safinamide + antidepressants group 4.30 (2.87)
HAMD-17 Mean (SD) Complete cohort 19.49 (4.03)
Safinamide-only group 18.39 (3.58)
Safinamide + antidepressants group 20.43 (4.20)
LEDD (mg) Mean (SD) Complete cohort 810.26 (368.45)
Safinamide-only group 681.25 (218.15)
Safinamide + antidepressants group 921.68 (432.86)
UPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.
brainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.
Antidepressant Drug Range of Doses (mg/day) n (%)
DULOXETINE 30–120 11 (25.0%)
ESCITALOPRAM 5–15 7 (15.9%)
MIRTAZAPINE 15–30 5 (11.4%)
SERTRALINE 50–100 5 (11.4%)
VENLAFAXINE 75–150 5 (11.4%)
TRAZODONE 50–100 4 (9.1%)
AMITRIPTILINE 25 1 (2.3%)
CLORIMIPRAMINE 25 1 (2.3%)
BUPROPION 150 1 (2.3%)
CITALOPRAM 20 1 (2.3%)
PAROXETINE + AMITRIPTILINE 10 + 25 1 (2.3%)
VENLAFAXINE + MIRTAZAPINE 75 + 15 1 (2.3%)
VORTIOXETINE 10 1 (2.3%)
brainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.
Baseline
Mean (SD) 1 Month
Mean Difference from Baseline (SD) p-Value 3 Months
Mean Difference from Baseline (SD) p-Value
HAMD-17 Complete cohort 19.49 (4.03)
n = 82 −6 (5.10)
n = 78 p < 0.0001 −7.27 (5.48)
n = 82 p < 0.0001
Safinamide 50 mg 18.50 (2.69)
n = 22 −3.32 (4.54)
n = 22 p = 0.0003 −4.73 (4.49)
n = 22 p < 0.0001
Safinamide 100 mg 19.85 (4.39)
n = 60 −7.03 (5.19)
n = 56 p < 0.0001 −8.02 (5.73)
n = 60 p < 0.0001
UPDRS I Complete cohort 4.56 (1.82)
n = 82 −1.32 (1.99)
n = 78 p < 0.0001 −1.5 (2.03)
n = 82 p < 0.0001
Safinamide 50 mg 4.59 (1.47)
n = 22 −0.64 (1.91)
n = 22 p = 0.0157 −0.91 (1.76)
n = 22 p = 0.0045
Safinamide 100 mg 4.55 (1.94)
n = 60 −1.59 (1.97)
n = 56 p < 0.0001 −1.72 (2.08)
n = 60 p < 0.0001
UPDRS II Complete cohort 13.59 (6.67)
n = 82 −2.51 (6.30)
n = 78 p < 0.0001 −2.47 (6.11)
n = 82 p < 0.0001
Safinamide 50 mg 11.50 (5.20)
n = 22 −0.36 (5.44)
n = 22 p = 0.4064 −0.23 (5.23)
n = 22 p = 0.4966
Safinamide 100 mg 14.35 (7.02)
n = 60 −3.30 (6.65)
n = 56 p < 0.0001 −3.28 (6.45)
n = 60 p < 0.0001
UPDRS III Complete cohort 22.91 (8.68)
n = 82 −3.58 (8.56)
n = 78 p < 0.0001 −4.03 (8.95)
n = 82 p < 0.0001
Safinamide 50 mg 22.00 (8.12)
n = 22 −0.41 (8.88)
n = 22 p = 0.7722 +0.50 (9.42)
n = 22 p = 0.6723
Safinamide 100 mg 23.25 (8.92)
n = 60 −4.8 (8.34)
n= 56 p < 0.0001 −5.70 (8.47)
n = 60 p < 0.0001
UPDRS IV Complete cohort 3.51 (2.83)
n = 82 −0.61 (2.61)
n = 78 p = 0.0003 −0.8 (2.53)
n = 82 p < 0.0001
Safinamide 50 mg 4.64 (2.59)
n = 22 −0.32 (2.38)
n = 22 p = 0.1839 −0.28 (2.50)
n = 22 p = 0.2482
Safinamide 100 mg 3.10 (2.82)
n = 60 −0.76 (2.50)
n = 56 p = 0.0007 −1.00 (2.28)
n = 60 p < 0.0001
HAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.
brainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.
1 Month 3 Months
Safinamide + Antidepressants Group
n = 42 Safinamide-only Group
n = 36 p-Value Safinamide + Antidepressants Group
n = 44 Safinamide-only Group
n = 38 p-Value
Major symptoms Confusion n (%) 2 (2.6%) 0 (0%) p = 0.564 1 (1.2%) 0 (0%) p = 1.251
Emotional lability 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 1 (1.2%) p = 0.627
Fever 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Sweating 3 (3.8%) 1 (1.3%) p = 0.627 3 (3.7%) 0 (0%) p = 0.266
Myoclonus 0 (0%) 0 (0%) - 2 (2.4%) 0 (0%) p = 0.565
Minor symptoms Agitation n (%) 2 (2.6%) 1 (1.3%) p = 1.021 1 (1.2%) 0 (0%) p = 1.251
Sleep disorders 13 (16.7%) 4 (5.1%) p = 0.053 13 (15.9%) 4 (4.9%) p = 0.054
Nervousness 15 (19.2%) 4 (5.1%) p = 0.017 13 (15.9%) 5 (6.1%) p = 0.108
Tachycardia 2 (2.6%) 1 (1.3%) p = 1.021 3 (3.7%) 0 (0%) p = 0.266
Hyperventilation 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Dyspnea 1 (1.3%) 2 (2.6%) p = 0.642 2 (2.4%) 3 (3.7%) p = 0.666
Diarrhea 0 (0%) 1 (1.3%) p = 0.897 1 (1.2%) 0 (0%) p = 1.251
Hypertension 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Hypotension 0 (0%) 0 (0%) - 0 (0%) 0 (0%) -
Ataxia 0 (0%) 1 (1.3%) p = 0.897 0 (0%) 1 (1.2%) p = 0.894
Data were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | The Prognostic Value of Whole-Blood PSMB5, CXCR4, POMP, and RPL5 mRNA Expression in Patients with Multiple Myeloma Treated with Bortezomib.
Proteasome inhibitors, like bortezomib, play a key role in the treatment of multiple myeloma (MM); however, most patients eventually relapse and eventually show multiple drug resistance, and the molecular mechanisms of this resistance remain unclear. The aim of our study is to assess the expression of previously described genes that may influence the resistance to bortezomib treatment at the mRNA level (ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1) and prognosis of MM patients. mRNA expression was determined in 73 MM patients treated with bortezomib-based regimens (30 bortzomib-sensitive and 43 bortezomib-refractory patients) and 11 healthy controls. RPL5 was significantly down-regulated in multiple myeloma patients as compared with healthy controls. Moreover, POMP was significantly up-regulated in MM patients refractory to bortezomib-based treatment. In multivariate analysis, high expression of PSMB5 and CXCR and autologous stem cell transplantation were independent predictors of progression-free survival, and high expression of POMP and RPL5 was associated with shorter overall survival.
1. Introduction
Multiple myeloma (MM, plasma cell myeloma) is a hematological malignancy characterized by the accumulation of malignant plasma cells (PC) in the bone marrow (BM), often resulting in bone lesions, hypercalcemia, infections, anemia, and production of monoclonal immunoglobulin [1]. The disease occurs mainly in older patients and accounts for 15% of all hematologic malignancies, with an annual incidence of 4.5–6 cases per 100,000 [2], with an estimated 32,270 new cases and 12,830 deaths in the United States in 2020 [3]. Proteasome inhibitors (PI) play a key role in the treatment of MM [4,5,6]. Three PIs, bortezomib, carfilzomib, and ixazomib, are currently approved for the treatment of MM and several others are undergoing clinical trials [7].
Bortezomib is the first-in-class selective and reversible inhibitor of the 26S proteasome. It demonstrates antiproliferative and antitumor activity, and its use has been a breakthrough in treating MM in the past 15 years [5]. It is a boronic acid-based compound, which inhibits β5 chymotrypsin-like (CT-L) and to a lesser extent, β1 caspase-like (C-L) of the proteasome; it has been approved for treatment both in front-line and in relapsed/refractory patients [7]. However, the development of resistance and side effects can limit its use in MM [8]. Most patients show resistance to bortezomib after several courses of treatment and most of them demonstrate multiple drug resistance. In addition, approximately 20% of patients exhibit primary resistance, which determines lack of response to treatment [8,9].
Although resistance to PIs appears to be acquired through a number of different mechanisms, genetic abnormalities play a key role for most anti-myeloma drugs [8,10,11,12]. Single-point mutations and modification of gene expression in neoplastic cells refractory to PI have been reported in previous studies [11,13,14,15,16]. Several genes associated with bortezomib resistance have been identified in MM cells, including POMP, XBP1, PSMB5, MARCKS, ABCB1, CXCR4, MAF, TXN, TJP1, RPL5, CDK5, and CYP1A1 [16,17,18,19,20,21,22,23]; however, these genes have been examined individually, and usually only using commercially available MM cell lines. The aim of our study was to evaluate the prognostic value of nine previously described genes that may affect the prognosis in patients with a clinically detected loss of response to bortezomib treatment: ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1. A better understanding of the genetic disorders involved in MM drug resistance can improve the prognosis and prognostication, and assist the development of new therapeutic options to improve the treatment of this disease.
2. Results
The demographic, clinical, and laboratory characteristics of the MM patients enrolled for the study are presented in Table 1. Overall, 30 of the 73 patients were bortezomib sensitive, while the other 43 were refractory. No statistically significant differences were observed between bortezomib-sensitive and bortezomib-refractory MM patients with regard to bone involvement at diagnosis (p = 0.96), calcium > 2.75 mmol/L at diagnosis (p = 0.89), creatinine > 2 mg/dL at diagnosis (p = 0.31) or Hb < 10 g/dL at diagnosis (p = 0.73) and ISS (p = 0.86). The only statistically significant difference was observed in predominant paraprotein level (p = 0.02). In addition, light chain disease (LCD) was more common (36.7%) among the sensitive group than the refractory group (9.3%).
Twelve patients had received at least one prior therapy before bortezomib-based regimen initiation and 11 of them had become refractory to bortezomib. It was found that 41 patients displayed IgG paraprotein, 17 demonstrated IgA, and 15 had LCD. Most of the patients (79.5%) had received a bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen, six (8.2%) VMP (bortezomib, melphalan, and prednisone), four (5.5%) VTD (bortezomib, thalidomide, and dexamethasone), another four VD (bortezomib and dexamethasone), and one received IsaVRd (isatuximab, lenalidomide, bortezomib, and dexamethasone). Cytogenetics data were available for 41 patients (56.1%). Amp (1q) was the most common abnormality (53.7%), followed by IGH rearrangements (46.3%), t(4;14) (22.0%), and del(13q) (19.5%).
A flowchart depicting the number of patients in all stages of the study, and giving reasons for exclusion, is presented in Figure 1. The expression of nine mRNAs (ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1) was determined in all 73 MM patients treated with bortezomib-based regimens and the 11 non-MM controls. Differential expression analysis indicated that RPL5 was significantly down-regulated in MM patients compared with controls (Table 2, Figure 2A). Moreover, POMP was significantly up-regulated in bortezomib-refractory MM patients (Table 3, Figure 2B). No statistically significant differences were found between the groups with regard to the expression of selected mRNAs and the quality of response to treatment (Tables S1 and S2).
To provide a unified assessment of the prognostic impact of selected mRNA expression level at diagnosis, twelve patients who had received prior treatment before the bortezomib-based regimen were excluded from the outcome analysis. In the course of multiple myeloma, the duration of response decreases consistently with each successive regimen [24]. In this way, previous treatment itself is a factor that severely impacts PFS. Data on PFS was available in 11/12 previously treated patients, and the impact of this factor is presented in Figure S1. In contrast, in the previously treated group, no statistically significant differences were observed in mRNA expression (Table S3); however, in order to increase the statistical power of the analysis, this group was not excluded from differential expression analyses.
Overall, data on progression free survival (PFS) were available for 49 patients and data on overall survival (OS) for 56 patients. The median PFS was 14.4 months and the median OS was 29.0 months. Univariate Cox proportional hazards regression analysis was conducted to determine the prognostic value of the quantified mRNA expression; the results indicated that in MM patients, higher expression of CXCR4, MARCKS, POMP, PSMB5, TXN, and XBP1 was significantly correlated with shorter PFS (Table 4, Figure 3). Univariate analysis found higher expression of POMP and RPL5 to be associated with shorter OS in MM patients (Figure 4). In addition, the only clinical variable that was related to PFS and OS was the use of autologous stem cell transplantation (ASCT) during the treatment schedule (Figure 5).
The PFS analyses included 12 cases of missing data. Therefore, to check its robustness, we repeated the univariate Cox regressions, including seven of the missing cases for which OS time was known. The analysis yielded similar hazard ratios and p-values as before, and the previously significant mRNAs maintained their significance (Table S4).
To further investigate the prognostic factors, multivariate analyses were carried out using Cox’s proportional hazards regression model with a stepwise selection procedure. As ASCT was the only significant clinical variable in our univariate analyses with proven prognostic significance, it was entered as covariate in the multivariable model. The results found high expression of PSMB5 and CXCR and the presence of ASCT to be the best independent predictors of PFS (Table 5). Multivariate analysis of OS found high expression of POMP and RPL5 to be associated with shorter survival.
We repeated our analyses with mRNA expression as a continuous variable (Table S5). In the univariate analyses, PSMB5 and CXCR4 lost their significance. In the next step, multivariate proportional hazard regression was performed with a stepwise selection procedure (Model 2, Table S6). An approach based on dichotomized variables yielded a model with a better fit to the data and with a lower AIC value.
3. Discussion
The study comprehensively determined the mRNA expression of nine genes that may affect resistance in 73 MM patients treated with bortezomib-based regimens and 11 healthy volunteers: ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1. The genes were selected on the basis of previous laboratory and clinical studies investigating the bortezomib resistance in MM patients [17,18,19,20,21,25]. For the present study, it was decided to evaluate the gene expression using whole-blood samples, as this is an easier procedure to perform in clinical practice than preliminary PC isolation. However, standardization of mRNA expression profiling after cytometric isolation of specific population of cells may be technically challenging because of the variability of material quality, cell number, and other factors important at this experimental scale (cell cycle, mutation profile, clonicity etc.). Moreover, designing a model based only on a selected population of cells could downplay the interactions between the cells and the immune system, as well as other unforeseeable effects. Restricting the analysis to a cell subset would therefore potentially result in a potentially, very accurate test if cells are isolated correctly, but not sufficiently robust to use in different settings, with different technical tools and in varying clinical scenarios. Although a functional analysis of how these genes change their activity within cells during different phases of treatment would be an exciting study to perform, it would likely require a different experimental model, cell cultures, and in-depth mechanistic evaluations far exceeding the scope of this survival-oriented analysis. A similar method but based only on leukocytes in peripheral blood, not whole blood, was recently used by Watanabe et al. in evaluating the novel biomarkers to predict bortezomib response in MM patients [26].
According to the differential expression analysis, RPL5 gene was the only gene that was significantly down-regulated in MM patients compared to the normal individuals; however, higher RPL5 expression correlated with shorter survival in MM patients. RPL5 has also been found to be deleted in 20–40% of MM patients, and it is the only recurrently mutated ribosomal protein gene in MM [27,28].
In addition, RPL5 mRNA expression level was proposed as a clinical biomarker for response to bortezomib in MM patients; Hofman et al. [28] reported significantly lower RPL5 mRNA expression in patients with MM who initially responded to bortezomib and then relapsed, and both newly diagnosed and relapsed patients with low RPL5 expression had better PFS when bortezomib was used in their treatment. In addition, they reported an association between low RPL5 mRNA levels and initial response to bortezomib in relapsed MM patients. RPL5 expression has also been associated with shorter survival in newly diagnosed patients [28].
In our study, POMP gene was significantly up-regulated in MM patients refractory to bortezomib-based treatment in comparison with bortezomib-sensitive patients. Higher expression of POMP was found to be associated with shorter survival: POMP protein expression is essential for the biogenesis of proteasome de novo and its increased expression facilitates acquired resistance to PI [16]. An increase in POMP protein expression has also been noted in V10R, RPMI 8226, OPM-2, ANBL-6, and KAS-6/1 MM cells resistant to bortezomib [16,29]. Similarly to the present study, POMP protein suppression via shRNAs restored cell sensitivity, while over-expression favored resistance.
A protein-binding site for a suppressive factor, NRF2, has also been identified in the promoter region of the POMP protein. Although its increased expression should increase sensitivity to bortezomib, expression of POMP has been found to be increased in resistant cells, together with increased levels of POMP protein. The activation of both proteins varies according to cell line, and POMP appeared to have a greater effect on bortezomib sensitivity in the KAS-6/1 than OPM-2 line [30].
In the MM patients in the present study, univariate Cox proportional hazards regression analysis found the expression of six of the nine studies genes, viz. PSMB5, CXCR4, MARCKS, POMP, TXN, and XBP1, to significantly correlate with PFS. In addition, the multivariate analysis found high expression of PSMB5, CXCR, and ASCT to be the best independent predictors of PFS. Proteasome subunit β type 5 (PSMB5) is the target for bortezomib and other PI inhibitors that harbor chymotrypsin-like proteolytic activity [31]. Bortezomib occupies the PSMB5 substrate-binding pocket, interfering with the catalytic N-terminal threonine residue. Apart from β5 point mutations, the most frequent change observed in the bortezomib-resistant cell lines was overexpression of the β5 subunit [21,32,33,34]. A recent study by Barrio et al. identified somatic PSMB5 substitutions in an MM patient treated with bortezomib, suggesting that resistance acquired through PSMB5 point mutations is clinically relevant [21]. Recently, in KMS-18 and KMS-27 MM cells, the PSMB5 gene was found to harbor novel bortezomib resistance alleles which determine response to second-generation proteasome inhibitors in MM [35]. In addition, PSMB5 deletion resensitized drug-resistant, PSMB5-mutated cell lines to bortezomib, suggesting that PSMB5 mutation plays a role in drug resistance [36].
Our findings indicated that higher CXCR4 expression correlated with shorter PFS. CXCR4 is a pleiotropic chemokine receptor which acts through its ligand (CXCL12) and influences proliferation, invasion, dissemination, and drug resistance in MM [37,38]. The current therapeutic focus is on disrupting the interaction of MM cells with their protective tumor microenvironment, in which the CXCR4 axis plays an essential role [39]. In contrast to our present study, reduced expression of CXCR4, a single biomarker in the Bcl-XL/Myc model system, has indicated poorer outcomes in MM patients treated with bortezomib [40]. In addition, low CXCR4 expression was associated with a worse outcome than high CXCR4 expression, and correlated with increased MM severity and aggressiveness in patients treated with bortezomib, either alone or in combination with other agents [18,40].
The univariate Cox proportional hazards regression analysis found that the higher expression of MARCKS, TXN, and XBP1 significantly correlated with shorter PFS in MM patients. Another marker of PI resistance is MARCKS. This protein is important in cell adhesion and metastatic spread [41] and is involved in resistance to apoptosis in prostate cancer cells [16]. Its expression is significantly elevated in many types of cancer [42]. Micallef et al. reported overexpression of MARCKS in nine of 18 (50%) studied MM cell lines [43]; in addition, in line with our present findings, Yang et al. reported increased MARCKS expression in bortezomib-refractory MM patients, as well as increased bortezomib sensitivity in bortezomib-resistant MM cells following inhibition of MARCKS phosphorylation [44]. Similar effects were achieved in an MM xenograft model [45].
A key role in bortezomib resistance is played by the increased expression of proteasomes and proteins involved in providing protection from oxidative stress, such as thioredoxin (TXN) [46]. Our findings indicate that higher expression of TXN correlates with shorter PFS. Previous studies have also found TXN to be overexpressed in primary myeloma cells isolated from bortezomib-resistant MM patients, and that overexpression of TXN correlated with poor overall survival in patients with MM [46]. In bortezomib-resistant myeloma cell lines, TXN inhibition overcomes adaptive bortezomib resistance [47]. In addition, higher TXN1 expression levels were found to correlate with myeloma cell survival and growth, and to protect MM cells against increased intrinsic oxidative stress [48]. Moreover, inhibition of TXN1 leads to apoptosis in drug-resistant MM.
Another gene whose high expression significantly correlated with shorter PFS in MM patients is XBP1, coding for X-box-binding protein 1. The XBP1 protein is an important transcription factor necessary for differentiation of B cells into plasma cells, being responsible for the final maturation of plasmablasts to plasmocytes and the induction of immunoglobulin secretion [49]. XBP1 is also a particularly important regulator in the UPR mechanism. It is spliced into two isoforms. One isoform, XBPs1s, activates the genes necessary to reduce ER stress and UPR activation after penetration into the cell nucleus. XBP1 may have a significant impact on resistance to bortezomib in MM cells. Low expression of XBPS1 has been associated with a lack of sensitivity to PI treatment [50]. Two point mutations in the XBP1 gene have been identified to date [49,51]: the first, XBP1-L167I, is located within the splice site of the XBP1 gene, and has been shown to prevent the XBP1 mRNA splicing process needed to form the active XBP1s protein, while the second, XBP1s-P326R, is located within the transactivation domain of the XBP1s molecule and has no effect on the splicing process. Cells displaying one of the described mutations lose their sensitivity to bortezomib, inducing disease resistance [52].
In conclusion, our results suggest that high expression of PSMB5 and CXCR may serve as predictors of PFS in MM patients treated with bortezomib-based regimens. In addition, high expression of POMP and RPL5 can be useful to predict shorter survival of these patients. However, further studies are needed to determine the role of these factors in effective strategy for improving anti-myeloma therapy.
4. Materials and Methods
4.1. Patients
The patients were recruited prospectively in our institution (Department of Hematology, Copernicus Memorial Hospital, Lodz, Poland) as a part of a planned marker study. The main exclusion criterion was using bortezomib-based therapy prior to the study. The main inclusion criteria were diagnosis of multiple myeloma according to International Myeloma Working Group (IMWG) criteria and planned treatment with a bortezomib-based regimen [53]. A total of 73 MM patients (43 men and 30 women) treated were included. The mean age of the group was 61.9 ± 10.8 years (range: 38.2 to 83.7 years). Their demographic, clinical, and laboratory details are shown in Table 1. All of the patients received bortezomib treatment as first-line treatment or in progression after previous therapy. The participants were classified as either bortezomib-sensitive or bortezomib-refractory, as previously reported, according to their response to bortezomib-based therapy [12,54]. Response to treatment and relapse/progression events were classified according to the IMWG [55,56].
The bortezomib-sensitive patients demonstrated CR, VGPR, or PR lasting longer than six months following discontinuation of bortezomib-based therapies [56,57,58]. In total, 30 patients were bortezomib refractory and 43 were bortezomib sensitive with no progression for at least six months of treatment discontinuation. The control group consisted of 11 healthy volunteers (six women and five men; mean age 61.9 ± 10.8 years; range: 38.2–83.7 years). The study was conducted according to good clinical and laboratory practice. The experimental protocol was conducted in accordance with the Declaration of Helsinki. All procedures were approved by the local ethical committee (The Ethical Committee of the Medical University of Lodz, No RNN/103/16/KE). Informed consent was obtained from all subjects involved in the study.
4.2. Blood Collection
Peripheral blood was collected in PAXgene Blood RNA Tubes (Qiagen, Germantown, MD, USA) from 73 multiple myeloma patients and 11 healthy volunteers and stored frozen at −80 °C. Venous blood samples were collected from MM patients, before treatment with bortezomib-based regimens, most commonly on the first day of the bortezomib administration. In previously treated MM patients, blood was collected at the time of progression, during the qualification process for commencement of a new therapy line.
4.3. The Analysis of Gene Expression Using Real-Time PCR
4.3.1. Isolation of Total RNA
Frozen blood samples were thawed on ice and total RNA was isolated from 1.5 mL of blood using the QIAamp RNA Blood Mini Kit (Qiagen) according to the manufacturer’s protocol. The final elution of total RNA was performed using 50 µL of RNase-free water. Total RNA quality was determined using the High Sensitivity RNA Screen Tape on a 2200 TapeStation bioanalyzer (Agilent, Santa Clara, CA, USA). The degradation rate of RNA was determined using RNA integrity number (RIN). Only the samples with RIN > 7 were further analyzed. The quantity of RNA was measured using NanoVue Plus Spectrophotometer (GE Healthcare, Wauwatosa, USA. Directly after isolation, RNA was used for the reverse transcription process.
4.3.2. Reverse Transcription Reaction
The reverse transcription was performed using the high-capacity cDNA reverse transcription kit (Applied Biosystems, ThermoFisher Scientific, Waltham, MA, USA,) according to the manufacturer’s protocol. The total volume of reverse transcription mix was 20 µL per reaction, containing 2 µL RT buffer (10X), 0.8 µL dNTP mixture (100 mM of each dNTP), 2 µL random primers (10X), 1 µL RNase inhibitor (20 U/µL), 1 µL MultiScribe Reverse Transcriptase (50 U/µL), and 10 µL RNA template, whereby the reagent mix was prepared on ice. The thermal profile of the reverse transcription program consisted of 10 min incubation at 25 °C, 120 min at 37 °C, 5 min reverse transcriptase inactivation at 85 °C, and cooling down to 4 °C. Total amount of 100 ng of RNA was used as a sample input per 20 µL of reverse transcription reaction. All reactions were performed in a 96-well SureCycler 8800 thermal cycler (Agilent, Santa Clara, CA, USA). The resulting cDNA was stored at −20 °C.
4.3.3. Selection of Reference Genes
A reference gene provides the internal control of the reaction and allows to determine the absolute and reliable value of the studied gene expression using real-time PCR. In order to normalize the variations in sample input for relative quantitation of gene expression, the selection of endogenous control genes was performed using the TaqMan™ Array Human Endogenous Control (Thermo Fisher Scientific, Waltham, MA, USA).
The analysis was performed for six total RNA samples isolated from whole blood of MM patients, according to the manufacturer’s protocol.
The stability of mRNAs was measured by NormiRazor [59]. This is an integrative tool which implements existing normalization algorithms (geNorm, NormFinder and BestKeeper) in a parallel manner. Three reference genes were selected by NormiRazor and TaqMan™ probes ((Thermo Fisher Scientific, Waltham, MA, USA) ACTB (Assay ID: Hs99999903_m1), RPLP0 (Assay ID: Hs99999902_m1), MT-ATP6 (Assay ID: Hs02596862_g1) and their average expression was used as reference.
4.3.4. Real-Time PCR
The expression of nine genes was analyzed in all samples: ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1. The analysis was performed using commercially available ready-to-use TaqMan® Assays (Applied Biosystems- Thermo Fisher Scientific, Waltham, MA, USA). These were preloaded with a probe labeled with 6-FAM™ dye (emission spectra at ~517 nm) and forward and reverse primers for the amplification of the following genes: ABCB1 (Assay ID: Hs00184500_m1), CXCR4 (Assay ID: Hs00976734_m1), MAF (Assay ID: Hs00193519_m1), MARCKS (Assay ID: Hs00158993_m1), POMP (Assay ID: Hs01106088_m1), PSMB5 (Assay ID: Hs00605652_m1, RPL5 (Assay ID: Hs00851991_u1), TXN (Hs00828652_m1), XBP1 (Assay ID: Hs00231936_m1).
The PCR mixture consisted of 10 µL of 2X TaqMan™ Genotyping Master Mix (Aplaied Biosystems-Thermo Fisher Scientific, Waltham, MA, USA), 1 µL of appropriate 20X TaqMan® Assay, and 1 µL of cDNA template. The mixture was filled up with a distilled, DNase- and RNase-free water (Gibco, Gaithersburg, MD, USA) to a final volume of 20 µL. The analysis was carried out using the TOptical thermal cycler (Analytik, Jena, Germany). The reactions were performed under the following conditions: an initial denaturation step at 95 °C for 10 min, followed by 40 amplification cycles of denaturation (95 °C, 15 s), a single annealing and extension step (60 °C for 1 min). Fluorescence signal detection was performed after each cycle. Gene expression analysis was performed for each sample in duplicates. Absolute quantification analysis was performed using qPCR Soft 3.1.15.0 (Analytik, Jena, Germany).
4.4. Statistical Analysis
4.4.1. Data Preparation
Data were normalized based on the mean expression of three mRNAs in a given sample (ACTB, RPLP0, MT-ATP6); this has proved to be the most stable normalization factor (according to NormiRazor). The normalized Ct values were calculated as:
Normalized ΔCt = Ct mRNA − (mean Ct of ACTB, RPLP0 and MT-ATP6)
Normalized ΔCt values for all samples and with class assignments were provided as Table S7.
4.4.2. Analysis
Nominal variables were expressed as percentages and analyzed using the Chi-square test with appropriate corrections if needed: the Yates correction for continuity or Fisher’s exact test.
For continuous variables, normally distributed data were tested using a two-sided independent Student’s t-test. Continuous variables were presented as mean ± standard deviation (SD) or medians with 25% to 75% values according to the data distribution. Survival analysis was conducted using a Kaplan–Meier estimate with univariate and multivariate Cox’s proportional hazards models, as well as the log-rank test. Cutoff Finder was used to determine the optimal cutpoint for gene expression dichotomization based on the log-rank test minimum p-value approach [60]. A procedure based on stratification of a continuous biomarker variable into two groups seems appropriate for use in clinics where most of the decisions are binary. Although such cutoffs are usually based on the mean or median value of the diagnostic factor, they can also be set based on the distribution of the variable or by optimizing the correlation with response to a treatment or outcome. A common problem in biomarker research is overestimating the actual effect when multiple cutoff points are investigated with no correction for multiple testing. The advantage of Cutoff Finder is that it determines the robustness of particular cutoff points and estimates the effect size with confidence intervals [60].
All statistical analyses were conducted using Statistica Version 13.1 (TIBCO, Palo Alto, CA, USA) and R programming language (version 4.0.2). p values lower than 0.05 were considered statistically significant. To control the family-wise error rate (FWER), the significant genes were chosen at 5% using Holm’s step-down method. FWER was used to insure a low probability of any false positives among the differentially expressed mRNA.
5. Conclusions
The present study examined the mRNA expression of nine genes with a possible influence on bortezomib sensitivity and refractoriness in MM, viz., ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1. Of these, RPL5 was down-regulated in MM patients as compared with the normal individuals. POMP was significantly up-regulated in MM patients refractory to bortezomib-based treatment. Multivariate analysis found that high expression of PSMB5 and CXCR and autologous stem cell transplantation were the best independent predictors of PFS, and that high expression of POMP and RPL5 were associated with shorter survival. The clinical and biological importance of these findings need further investigation.
Acknowledgments
We thank Edward Lowczowski from the Medical University of Lodz for editorial assistance and Andrzej Berut from Bionanopark, Lodz for administrative support.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/951/s1. Supplementary Table S1: ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1 mRNA expression in MM patients with complete remission (CR) to bortezomib-based chemotherapy and those without. Supplementary Table S2: ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1 mRNA expression in MM patients with at least very good partial response (VGPR), partial response, stable disease, or disease progression (<VGPR) after bortezomib-based treatment. No difference was found between the two groups. Supplementary Table S3: mRNA expression in treatment-naive and previously treated MM patients. A higher ΔCt value represents lower expression of the gene at the mRNA level. Supplementary Table S4: Univariate Cox regression analyses for progression-free survival with missing data (n = 7) replaced by overall survival. Supplementary Table S5: Univariate Cox regression analyses for progression-free survival and overall survival- mRNAs expression as continuous variables. Supplementary Table S6: Comparison of final Cox regression of multivariate models based on dichotomized variables (model 1) and continuous variables (model 2). Supplementary Table S7: Normalized ΔCt of mRNA expression for all samples and with class assignments. Supplementary Figure S1: Kaplan–Meier plots for previous treatment and treatment-naïve groups in the univariate analysis for PFS.
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Author Contributions
Conceptualization, P.R., I.D., J.S. and T.R.; methodology, P.R., I.D., D.J., D.M., A.K., M.M., K.S., W.F., J.S., P.S. and T.R.; software, P.R., D.J., D.M., A.K., W.F., J.S., P.S.; validation P.R., D.M. and T.R.; formal analysis, P.R., D.M., K.S.; W.F. D.J. and T.R.; investigation P.R., D.J., M.M.; E.W.; A.K. and I.D.; resources, T.R.; P.R. and J.S; data curation, P.R., I.D., D.M.; writing— P.R., I.D., D.J., D.M. and T.R.; writing—review and editing, P.R., I.D., D.J., D.M. P.S., J.S. E.W. and T.R.; visualization, P.R., D.J., D.M. and T.R.; supervision, T.R.; project administration, T.R.; P.R. and I.D.; funding investigation, T.R.; P.R. and I.D.; resources, P.R.; I.D. and T.R. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by a grant from the NCN (2016/23/B/NZ5/02529).
Institutional Review Board Statement
The experimental protocol was conducted in accordance with the Declaration of Helsinki. All procedures were approved by the local ethical committee (The Ethical Committee of the Medical University of Lodz, No RNN/103/16/KE).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Data is contained within the article or supplementary material are available according to “MDPI Research Data Policies” at https://www.mdpi.com/journal/cancers/ instructions#suppmaterials. Normalized ΔCt of mRNA expression for all samples with class assignments are provided in Supplementary Table S7.
Conflicts of Interest
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Abbreviations
ABCB1 Adenosine-triphosphate-binding cassette sub-family B member 1
ACTB beta-actin gene
ASCT autologous stem cell transplantation
BM bone marrow
CXCR-4 C-X-C chemokine receptor type 4
DLBCL diffuse large B-cell lymphoma
ECM extracellular matrix
FWER family-wise error rate
IPO8 Importin 8 gene
IsaRVD isatuximab, lenalidomide, bortezomib, dexamethasone
MAF musculoaponeurotic fibrosarcoma
MARCKS myristoylated alanine-rich C-kinase substrate
MM multiple myeloma
MT-ATP6 mitochondrially Encoded ATP Synthase Membrane Subunit 6 gene
NRF2 nuclear factor erythroid 2-related factor 2
NF-κB nuclear factor kappa B
OS overall survival
PC plasma cells
POMP proteasome maturation protein
PFS progression free survival
PI proteasome inhibitor
PSMB5 proteasome subunit β type 5
RPLP0 Ribosomal Protein Lateral Stalk Subunit P0 gene
RPL5 ribosomal protein L5
UPR unfolded protein response
TXN thioredoxin
VCD bortezomib, cyclophosphamide, dexamethasone
VD bortezomib and dexamethasone
VMP bortezomib, melphalan and prednisone.
VTD bortezomib, thalidomide, dexamethasone
TXN thioredoxin
XBP1 X-box binding protein 1
Figure 1 Flowchart of study protocol and main analyses. Abbreviations: CR—complete response; MM—multiple myeloma; OS—overall survival; PFS—progression-free survival.
Figure 2 Dot plot representation of the ΔCt values of differentially expressed mRNA. The box plots depict the mean and SD. A higher ΔCt value represents the lower expression of the gene at the mRNA level: (A) ΔCt of RPL5 in multiple myeloma patients healthy donors (p = 0.0033) and (B) ΔCt of POMP in sensitive and refractory to bortezomib MM patients (0.0062).
Figure 3 Kaplan–Meier plots for each of the significant mRNAs in the univariate analyses for PFS: (A) CXCR4, (B) MARCKS, (C) POMP, (D) PSMB5, (E) TXN, (F) XBP1.
Figure 4 Kaplan–Meier plots for each of the significant mRNAs in the univariate analyses for OS: (A) POMP, (B) RPL5.
Figure 5 Kaplan–Meier plots for ASCT in the univariate analyses for (A) PFS and (B) OS.
cancers-13-00951-t001_Table 1 Table 1 The characteristics of the MM patients treated with bortezomib-based therapy and healthy donors. Data are presented as frequency, percentage (%) unless otherwise specified.
Variable MM Total Refractory Sensitive Healthy Donors p
Number of patients 73 43 30 11 -
Gender (%)
N (%) M: 43 (58.9)
F: 30 (41.1) M: 25 (58.1)
F: 18 (41.9) M: 18(60.0)
F: 12(40.0) M: 5 (45.5)
F: 6 (54.5) 0.69
Age + SD (range) 61.9 ± 10.8
(38.2–83.7) 62.2 ± 11.5
(38.2–83.7) 61.3 ± 9.7
(39.8–81.6) 63.0 ± 6.2
(52.6–74.4) 0.73
Bortezomib regimen: - - - - 0.18
VCD 58 (79.5) 32 (74.4) 26 (86.7) -
VMP 6 (8.2) 5 (11.6) 1 (3.3) -
VTD 4 (5.5) 2 (4.7) 2 (6.7) -
VD 4 (5.5) 4 (9.3) 0 -
IsaVRD 1 (1.4) 0 1 (6.7) -
Paraprotein–N (%) - - - - 0.02
IgG 41 (56.2) 28 (65.1) 13 (43.3)
IgA 17 (23.3) 11 (25.6) 6 (20.0) -
LCD 15 (20.5) 4 (9.3) 11 (36.7) -
Prior treatment 12 (16.4) 11 (25.6) 1 (3.3) - 0.01
Bone involvement at diagnosis 40 (54.8) 23 (53.5) 17 (56.6) - 0.96
Calcium > 2.75 mmol/L at diagnosis 12 (16.4) 7 (16.3) 5 (16.7) - 0.89
HB < 10g/dL at diagnosis 26 (35.6) 14 (32.6) 12 (40.0) - 0.73
Creatinine > 2 mg/dL at diagnosis 10 (13.7) 4 (9.3) 6 (20.0) - 0.31
International Staging System (ISS) at diagnosis I: 22 (30.1)
II: 17 (23.3)
III:32(43.8) I: 14 (32.6)
II: 10 (23.3)
III: 18(41.9) I: 8 (26.7)
II: 7 (23.3)
III: 14(46.7) - 0.86
CRP > 5 mg/L 33 (45.2) 16 (37.2) 17 (56.7) - 0.06
Beta2-microglobuline increased (>3mg/L) 51 (69.9) 31 (72.1) 20 (66.7) - 0.36
LDH > 240U/L 9 (12.3) 5 (11.6) 4 (13.3) - 0.85
Cytogenetics (%) N = 41 N = 24 N = 17 -
t(4;14) 9 (22.0) 7 (29.2) 2 (11.8) 0.26
t(14;16) 0 0 0 -
t(14;20) 0 0 0 -
del(17p) 6 (14.6) 4 (16.7) 2 (11.8) 1.00
amp(1q) 22 (53.7) 12 (50.0) 10 (58.8) 0.75
del(13q) 8 (19.5) 2 (8.3) 6 (35.3) 0.61
t(11; 14) 1 (2.4) 1 (4.2) 0
del(1p) 2 (4.9) 1 (4.2) 1 (5.9) 1.00
IGH rearrangements 19 (46.3) 12 (50.0) 7 (41.2) 0.71
Abbreviations: CRP—c-reactive protein; IGH—immunoglobulin heavy chain; LCD—light chain disease; IsaVRD—isatuximab, lenalidomide, bortezomib, dexamethasone; LDH—lactate dehydrogenase; MM—multiple myeloma; VCD—bortezomib, cyclophosphamide, dexamethasone; VD—bortezomib and dexamethasone: VMP—bortezomib, melphalan and prednisone; VTD—bortezomib, thalidomide, dexamethasone.
cancers-13-00951-t002_Table 2 Table 2 mRNA expression in multiple myeloma patients and healthy donors. The higher ΔCt value represents the lower expression of gene at mRNA level.
mRNA ΔCt MM
(N = 73)
mean ± SD Δ Ct Healthy Donors (N = 11)
Mean ±SD FC p-Value FWER
ABCB1 7.55 ± 0.99 7.12 ± 0.74 0.74 0.1075 0.6451
CXCR4 3.83 ± 0.82 3.56 ± 0.21 0.82 0.0209 0.1669
MAF 7.75 ± 1.08 7.20 ± 0.85 0.68 0.0737 0.5159
MARCKS 5.99 ± 0.83 5.63 ± 0.90 0.78 0.2346 1.0000
POMP 5.17 ± 0.67 5.12 ± 0.39 0.97 0.7541 1.0000
PSMB5 6.96 ± 0.78 6.80 ± 0.59 0.90 0.4341 1.0000
RPL5 2.73 ± 0.81 2.02 ± 0.46 0.61 0.0004 0.0033
TXN 3.43 ± 0.74 3.69 ± 0.66 1.20 0.2508 1.0000
XBP1 3.26 ± 0.92 3.21 ± 0.66 0.96 0.8036 1.0000
Abbreviations: MM—multiple myeloma; FC—fold change; FWER—family-wise error rate.
cancers-13-00951-t003_Table 3 Table 3 mRNA expression in MM patients sensitive and refractory to bortezomib-based chemotherapy. The higher ΔCt value represents the lower expression of gene at mRNA level.
mRNA ΔCt Refractory (N = 43)
Mean ± SD ΔCt Sensitive (N = 30)
Mean ± SD FC p-Value FWER
ABCB1 7.58 ± 1.02 7.50 ± 0.98 0.95 0.7384 1.0000
CXCR4 3.75 ± 0.70 3.95 ± 0.96 1.15 0.3438 1.0000
MAF 7.70 ± 1.12 7.82 ± 1.03 1.09 0.6516 1.0000
MARCKS 5.79 ± 0.70 6.27 ± 0.92 1.40 0.0190 0.1522
POMP 4.94 ± 0.57 5.48 ± 0.67 1.45 0.0007 0.0062
PSMB5 6.84 ± 0.70 7.12 ± 0.87 1.22 0.1421 0.8523
RPL5 2.69 ± 0.87 2.78 ± 0.75 1.06 0.6622 1.0000
TXN 3.35 ± 0.72 3.55 ± 0.77 1.15 0.2676 1.0000
XBP1 3.08 ± 0.84 3.51 ± 0.97 1.35 0.0537 0.3759
Abbreviations: MM—multiple myeloma; FC – fold change; FWER—family-wise error rate.
cancers-13-00951-t004_Table 4 Table 4 Univariate Cox regression analyses for progression-free survival and overall survival.
Variables PFS OS
Coefficient p-Value HR 95% CI Coefficient p-Value HR 95% CI
Lower Upper Lower Upper
ABCB1 expression (high vs. low) −0.248 0.2716 0.609 0.252 1.474 −0.226 0.2950 0.637 0.273 1.482
CXCR4 expression (high vs. low) 0.571 0.0327 3.134 1.099 8.940 0.272 0.2865 1.722 0.634 4.679
MAF expression (high vs. low) 0.261 0.1348 1.685 0.850 3.336 0.390 0.2968 2.183 0.504 9.464
MARCKS expression (high vs. low) 0.594 0.0018 3.281 1.559 6.907 −0.343 0.1115 0.504 0.217 1.172
POMP expression (high vs. low) 0.409 0.0236 2.266 1.116 4.601 0.573 0.0108 3.144 1.303 7.585
PSMB5 expression (high vs. low) 0.476 0.0088 2.591 1.271 5.280 0.348 0.1497 2.004 0.778 5.158
RPL5 expression (high vs. low) −0.137 0.4206 0.760 0.389 1.483 0.641 0.0035 3.607 1.526 8.524
TXN expression (high vs. low) 0.394 0.0290 2.198 1.084 4.456 0.298 0.1683 1.813 0.778 4.228
XBP1 expression (high vs. low) 0.479 0.0099 2.605 1.259 5.389 0.270 0.2091 1.715 0.739 3.981
Age 0.006 0.7070 1.006 0.975 1.038 0.037 0.1281 1.038 0.989 1.089
ASCT
No Reference Reference
Yes −0.487 0.0089 0.378 0.182 0.783 −0.624 0.0157 0.287 0.104 0.790
Bone involvement at diagnosis
No Reference Reference
Yes 0.303 0.1043 1.832 0.882 3.805 0.309 0.1932 1.856 0.731 4.709
Calcium > 2.75 mmol/L at diagnosis
No Reference Reference
Yes 0.374 0.0929 2.112 0.883 5.052 −0.089 0.7501 0.837 0.281 2.495
CRP >5 mg/L
No Reference Reference
Yes 0.101 0.6100 1.224 0.563 2.663 −0.461 0.0637 0.398 0.150 1.054
HB < 10 g/dL at diagnosis
No Reference Reference
Yes 0.092 0.6243 1.202 0.576 2.505 0.009 0.9698 1.018 0.409 2.530
ISS I Reference Reference
ISS II −0.682 0.0590 0.375 0.124 1.134 0.030 0.9389 1.828 0.460 7.267
ISS III 0.383 0.1594 1.089 0.509 2.326 0.544 0.0684 3.056 1.035 9.021
Creatinine > 2 mg/dL at diagnosis
No Reference Reference
Yes −0.396 0.1952 0.453 0.136 1.502 −0.253 0.4984 0.603 0.140 2.606
LDH >240U/L
No Reference Reference
Yes 0.188 0.4221 1.457 0.581 3.651 0.411 0.1526 2.277 0.737 7.032
Gender
F Reference 0.1008 0.564 0.284 1.118 Reference
M −0.287 0.352 0.1583 2.022 0.760 5.376
Abbreviations: ASCT—autologous stem cell transplantation; CRP- c-reactive protein; CXCR-4—C-X-C chemokine receptor type 4; FWER—family-wise error rate: HB—hemoglobin; ISS—International scoring system; LDH—lactate dehydrogenase; MM—multiple myeloma; OS—overall survival; PFS—progression free survival.
cancers-13-00951-t005_Table 5 Table 5 Final multivariate Cox regression analyses for PFS and OS of MM patients.
Variables PFS
Coefficient p-Value HR 95% CI
Lower Upper
PSMB5 expression (high vs. low) 0.386 0.0451 2.164 1.017 4.603
CXCR expression (high vs. low) 0.748 0.0073 4.465 1.496 13.320
ASCT
No Reference
Yes −0.612 0.0024 0.294 0.133 0.649
Variables OS
POMP expression (high vs. low) 0.523 0.0258 2.849 1.135 7.148
RPL5 expression (high vs. low) 0.664 0.0026 3.777 1.591 8.963
Abbreviations: ASCT—autologous stem cell transplantation; HR—hazard ratio; MM—multiple myeloma; OS—overall survival; PFS—progression free survival.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BORTEZOMIB | DrugsGivenReaction | CC BY | 33668794 | 19,174,581 | 2021-02-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile neutropenia'. | Under-Treatment of Older Patients with Newly Diagnosed Epithelial Ovarian Cancer Remains an Issue.
Older women with ovarian cancer have disproportionately poorer survival outcomes than their younger counterparts and receive less treatment. In order to understand where the gaps lie in the treatment of older patients, studies incorporating more detailed assessment of baseline characteristics and treatment delivery beyond the scope of most cancer registries are required. We aimed to assess the proportion of women over the age of 65 who are offered and receive standard of care for first-line ovarian cancer at two UK NHS Cancer Centres over a 5-year period (December 2009 to August 2015). Standard of care treatment was defined as a combination of cytoreductive surgery and if indicated platinum-based chemotherapy (combination or single-agent). Sixty-five percent of patients aged 65 and above received standard of care treatment. Increasing age was associated with lower rates of receiving standard of care (35% > 80 years old versus 78% of 65-69-year-olds, p = 0.000). Older women were less likely to complete the planned chemotherapy course (p = 0.034). The oldest women continue to receive lower rates of standard care compared to younger women. Once adjusted for Federation of Gynaecology and Obstetrics (FIGO) stage, Eastern Cooperative Oncology Group (ECOG) performance status and first-line treatment received, age was no longer an independent risk factor for poorer overall survival. Optimisation of vulnerable patients utilising a comprehensive geriatric assessment and directed interventions to facilitate the delivery of standard of care treatment could help narrow the survival discrepancy between the oldest patients and their younger counterparts.
1. Introduction
Ovarian cancer (including primary peritoneal and fallopian tube cancer) is predominantly diagnosed in older women with around half of all new diagnoses occurring in women over the age of 65. Older patients are less likely to be enrolled in clinical trials [1,2] that go onto to shape current gold standards. Treatment decisions are usually based on clinical trial results, which include a younger, less frail population and are applied to an older and often less well group. The efficacy and tolerability of standard of care and novel therapies in an older, potentially frailer population are therefore not clearly understood.
It has long been shown that survival outcomes are disproportionately lower in older patients [3] and delayed diagnosis/late presentation [4], more advanced disease at diagnosis [5,6,7], higher rates of emergency presentation [8], higher rates of unclassified or unclassifiable tumours [3] as well as lower physical performance status and higher prevalence of medical and functional comorbidities [9] contribute to this. Recent studies have reported high rates of no recorded treatment in older patients, for example 60% of ovarian cancer patients aged over 79 had no record of any treatment in England between 2016 and 2018 [10,11]. Developing our understanding of the “real-world” experience of treatment for ovarian cancer in an older population is necessary. Until the reasons for the difference in survival between older and younger women are more clearly understood, efforts to address the gaps and improve outcomes in our older population will be hampered. Large-scale cancer registry data by both the EUROCARE [12,13,14,15] series and the International Cancer Benchmarking Partnership (ICBP) [6,7,16,17] demonstrate that both short and long-term survival outcomes in older women continue to be significantly inferior to those seen in middle-aged and younger women [12,17,18]. Notably, an improving trend in 1- and 5-year survival for all age groups has been reported excepting those aged over 75 years [19].
The field of geriatric oncology has rapidly developed over the last two decades. The core principles outline the need to holistically assess patients using a comprehensive geriatric assessment rather than basing treatment decisions purely on chronological age. Both the International Society of Geriatric Oncology (SIOG) [20] and the American Society of Clinical Oncology (ASCO) [21] have now recommended that geriatric assessment (GA) be undertaken in all adults aged 65 years and over being considered for systemic anti-cancer therapy. Crucially, clinicians should implement GA-directed interventions in order to optimise patient care.
2. Results
2.1. Patient Baseline Characteristics
Two hundred and eighty patients met the inclusion criteria. Patients were divided into four age cohorts (65–69 years, 70–74 years, 75–79 years and >80 years). The majority (76%) of patients had stage 3 or 4 disease at presentation (Table 1). Stage distribution did not alter with increasing age (p = 0.293). 29% of patients were ECOG performance status 2 or 3. Increasing age was significantly associated with a worsening ECOG performance status (p = 0.008). Forty-nine percent of patients over the age of 80 were PS 0 or 1 compared to 70.4% of patients in the 65–69 years cohort (Table 1). The majority (69.6%) of patients were diagnosed with high-grade serous carcinoma. Histological subtype did not vary according to age (p = 0.547).
The most commonly documented comorbidities were cardiovascular disease (27.5%), hypertension (40.4%), respiratory disease (10%) and diabetes (10.4%). Polypharmacy at the initial consultation, defined as taking 3 or more daily prescribed medications, was present in 40% of patients. Neither cardiovascular disease nor hypertension was associated with increasing age. 48.9% women were anaemic (any grade) at baseline with 11.4% patients having a Grade 2 or higher anaemia. Impaired renal function at the start of treatment was also common with 37% of all patients having at least a mild-moderate reduction of glomerular-filtration rate (GFR) of 60 mL/min or less, amounting to chronic kidney disease grade 3. A total of 40.7% patients had an albumin below 35 g/L at baseline and 22.5% of patients had an albumin less than 30 g/L. Hypoalbuminaemia was not associated with increasing age (p = 0.36) (Table 2). Factors and comorbidities significantly associated with advancing age were polypharmacy (p = 0.01), respiratory disease (p = 0.007) and cognitive impairment (p = 0.001) (Table 2.) Increasing age was associated with a higher proportion of women living alone (51% of those >80 years compared with 22% of those aged 65–69 years, p = 0.000). Older women were also significantly more likely to live in supported accommodation (p = 0.032), use a walking aid (p = 0.026) or have a degree of visual impairment (p = 0.016). A quarter of all patients reported reduced activities of daily living in the weeks and months preceding their diagnosis. Self-reported weight loss was also prevalent with 23.6% of patients reporting weight loss over the 3 months prior to their diagnosis (Table 2.)
2.2. First Line Treatment
Sixty-five percent of patients received standard of care cytoreductive surgery and platinum-based chemotherapy in keeping with the European Society of Medical Oncolgogy ESMO)-European-Society of Gynaecological Oncology (ESGO) consensus recommendations [22]. Increasing age was associated with reducing rates of receiving standard of care therapy with 35.1% of those over the age of 80 receiving both chemotherapy and surgery compared to 78% in those aged 65–69 years (p = 0.000). Ten percent of patients over the age of 80 received no cancer treatment (Figure 1). Six (2%) patients declined surgery and three (1%) declined chemotherapy. Increasing age was associated with lower rates of undergoing cytoreductive surgery (p = 0.001) as well as complete cytoreduction (defined according to the post-operative report) (p = 0.006) with complete cytoreduction obtained in only 28% of those over the age of 80 compared to 69% in those aged 65–69. When optimal cytoreduction (<1 cm residual disease) is reported as a proportion of those patients who underwent surgery, the rates of optimal cytoreduction was 76% in all age cohorts apart from those over 80 where it was 49%. 53.7% of women received standard carboplatin and paclitaxel chemotherapy as first-line treatment. Older women were less likely to receive doublet chemotherapy (19.3% in those over the age of 80 compared to 73.6% in those aged 65–69 years, p = 0.000). Overall, 7.8% women aged 65 and above any form of targeted therapy during first-line treatment. This proportion decreased with advancing age (2.3% of women over the age of 80 compared to 12.4% women between the ages of 65–69 received some form of targeted therapy during first-line treatment (p = 0.05).
Subsequently, the primary treatment of only those women with advanced (Federation of Gynaecology and Obstetrics (FIGO) stage III/IV) disease was assessed. A total of 62.9% of women aged 65 and over received standard of care, with this proportion decreasing significantly with increasing age (p = 0.000). 46.3% of women aged 80 years and over underwent cytoreductive surgery. In these women complete cytoreduction was achieved in 31.6%, compared to those aged between 65–69 years of whom 82.4% underwent surgery, and 69.6% had complete cytoreduction (p = 0.014).
2.3. Treatment Tolerance
Overall, 27.3% of patients developed a grade two or higher haematological toxicity. Neutropenia was more common in younger patients (69.6% in those aged 65–69 vs. 18.8% in those aged 75–79, p = 0.007). Older patients did not experience higher rates of severe haematological toxicity (p = 0.554). However, increasing age was associated with a trend towards a higher rate of G3 or 4 non-haematological toxicities although this did not reach statistical significance (32.5% vs. 13.4% in those aged >80 years vs. those aged 65–69 years, p = 0.082). Increasing age was significantly associated with a lower likelihood of completing 6 cycles (p = 0.034). Of the 38 (15.8%) women who discontinued treatment early, 21 (55%) did so because of toxicity. Discontinuation due to toxicity was higher in older patients, for example 54.5% of 75–79-year-olds compared to 36.4% of those aged 65–69 years, although this did not reach statistical significance (p = 0.15). 28.5% of all patients were admitted to hospital as an emergency at some stage during their primary treatment with no variation due to age (p = 0.135), 30-day mortality was 1.24% across the whole cohort and did not vary according to age (p = 0.184) (Table 3).
2.4. Treatment at Relapse
At first relapse, 50.4% of women received chemotherapy; however, older women were significantly less likely to receive second-line chemotherapy at progression. A total of 35.5% of women over the age of 75 received chemotherapy at relapse, compared to 62.5% of those aged 65–69 years (p = 0.021). One patient (aged 75 years) underwent secondary debulking surgery. Seventy-five women (59% of those who had treatment for relapsed disease) received carboplatin-based chemotherapy at first relapse. Of those who received chemotherapy at first relapse, 56 (45%) received a carboplatin doublet regimen (paclitaxel, pegylated liposomal doxorubicin or gemcitabine with or without a targeted agent for example, bevacizumab). Nineteen (15%) women received single-agent carboplatin. Of those who received platinum at first relapse, 65% achieved some degree of tumour shrinkage as their best response according to the local radiological report with 89% achieving at least stable disease. In those patients who received non-platinum containing regimens, 21 patients (15%) received weekly paclitaxel resulting in a 33.3% radiological response rate and a 52% clinical benefit rate (defined as patients who achieved at least stable disease as their best response documented). Twenty-three (18.9%) patients received either pegylated liposomal doxorubicin or doxorubicin. No responses were seen in this group although 6 (26%) patients had stabilisation of their disease.
2.5. Survival Outcomes
Median overall survival (OS) for all patients was 31.5 months. For patients diagnosed with stage III and stage IV disease, median OS was 28.3 and 14 months respectively. 1-year and 5-year survival was 78.1% (95% CI 72.7–82.5) and 28.7% (95% CI 22.5–35.2) respectively. Overall survival was broadly equivalent over the first three age cohorts however patients over the age of 80 had a significantly lower survival than those aged 65–69 years (median OS 20.02 months vs. 44.91 months, p = 0.000) (Figure 2). First line carboplatin/paclitaxel combination chemotherapy was associated with improved survival outcomes compared to single-agent carboplatin (OS 39.5 vs. 30.6 months), those patients who received no chemotherapy had an OS of 9.7 months (p = 0.003). Progression-free survival (PFS) was similar across all age groups up to the age of 80 but patients aged 80 years and over had a median PFS of 12.3 months compared to 16.4 in those aged 65–69 years (HR 2.0 p = 0.00) (Figure 2).
In univariate analysis, age over 80 years at diagnosis, FIGO stage III/IV disease, incomplete cytoreduction and an ECOG PS of greater than 1 were all associated with poorer survival outcomes. Of the baseline factors and comorbidities collected, the presence of cardiovascular disease (p = 0.043), polypharmacy (p = 0.011) or having a current or past history of smoking (p = 0.008) were all associated with poorer survival outcomes. Requiring assistance with activities of daily living (ADL) (p = 0.000), reporting reduced ADLS (p = 0.000) and weight loss at diagnosis (p = 0.015) were associated with poorer survival outcomes (Table 4). Of the biochemical parameters collected, having any degree of hypoalbuminaemia (p = 0.000) or baseline haemoglobin of less than 110 g/L (p = 0.000) were associated with poorer survival outcomes. GFR was associated with poorer survival as a continuous variable (p = 0.036) however using a threshold of a GFR of 60 mL/min (CKD 3) was not associated with poorer survival outcomes (p = 0.064) (Table 4).
A cox proportional hazards multivariate model was built including treatment-related factors that were predictive, by univariate analysis for overall survival. When adjusted for FIGO stage, surgical outcome, chemotherapy treatment and completion of chemotherapy, age over 80-years-old was no longer an independent risk factor for poorer overall survival. Completion of chemotherapy remained independently associated with overall survival where single-agent versus platinum-doublet chemotherapy was not associated with a significantly different in overall survival in either univariate or multivariate analysis (Table 5).
3. Discussion
This study provides a useful insight into the current real-world treatment of older women diagnosed with epithelial ovarian cancer in two UK cancer centres. There were very low rates of unclassifiable tumours in this series compared to national cancer registry data where over 50% of women over the age of 80 had an unclassified epithelial or miscellaneous tumour [3]. The lack of relationship between unclassifiable tumours and increasing age suggests either an improvement in the approach to the diagnostic process in older patients with more women having a true histological diagnosis being pursued, or the importance of cancer centre management of presumed ovarian cancer. Delayed time to diagnosis and therefore later stage at diagnosis has also been postulated as a cause for poorer survival rates however, stage distribution also did not vary with age in this population with the majority of women of all ages being diagnosed with stage 3 and 4 disease.
In this series, older patients were more likely to have a poorer ECOG performance status however it is well recognised that ECOG performance status alone is a crude measure in an elderly population that does not accurately reflect the functional and comorbid status of older patients [23,24] and it has also been previously shown that poor performance status should not necessarily preclude first-line treatment in epithelial ovarian cancer due to the high response rates observed to platinum-based chemotherapy [25]. Although many older women maintain fit and active lives, a quarter of the study population reported reduced activities of daily living in the preceding weeks and months before their diagnosis. A significant proportion of women in this study also reported living alone, whilst not a concern in and of itself, living alone without sufficient social network or community support particularly in the context of frailty is a challenge for both patients and oncologists when systemic anti-cancer therapy is being considered.
The most striking difference between the oldest patients and those younger than 80 years was that seen in primary treatment received. Under-treatment has long been postulated as one of the primary reasons for the poorer outcomes in older patients. A large retrospective study in France assessed the impact of age on treatment and survival outcomes whether or not guideline-recommendations for therapy were followed between 1997 and 2011. Women 70 years and over compared to those younger were less likely to undergo surgery (60.9% versus 89.6%, p < 0.0001) or receive chemotherapy (57.4% versus 76.4%, p < 0.0001). Only 31.9% of patients 70 years and over underwent both surgery and chemotherapy [26]. A prospective study (OVCAD) that included 275 women treated for primary ovarian cancer between 2005 and 2008 also showed that older women were less likely to receive optimal therapy and had poorer progression-free and overall survival. In multivariate analysis, age was an independent risk factor for poorer overall but not progression-free survival [27]. Our findings confirm that older women continue to receive less treatment than their younger and middle-aged counterparts and this is likely to be a significant factor in explaining the poorer outcomes seen in this population. A limitation of this work is that it was not possible from this retrospective study to ascertain whether, in those patients who did not receive either surgery or chemotherapy whether this decision was patient or clinician-led. Documentation of the rationale for a decision for not treatment should be consistently recorded in patient records. In addition, interview studies of the multidisciplinary team making treatment decisions may shed more light on the rationale for patients not receiving standard of care. It has previously been shown that older women desire cure as much as their younger counterparts and are more willing to undergo potentially disfiguring surgery to achieve this than younger patients [28]. In work also undertaken by our group (manuscript under review), we report that older patients desired active treatment and did not consider their age to be a hindrance.
The difference in survival for the oldest patients becoming no longer statistically significant once FIGO stage, surgical outcome and crucially, chemotherapy received are incorporated into the model provides further evidence that if even the oldest patients receive optimal therapy, survival outcomes are comparable. It has been shown that medical and social optimisation of older patients prior to and during systemic anti-cancer therapy can improve chemotherapy completion rates [29]. This approach is being tested in a wider scale in both the PREPARE [30] and GIVE (NCT02785887) studies; these potentially practice-changing results are awaited. We report here that older patients were less likely to receive targeted therapy, however, the only targeted therapy available during the study period was bevacizumab, which only received NICE approval in 2013 (i.e., the final two years of the study period) and thus these rates may not be fully representative.
Haematological toxicity rates were comparable across the age groups however increasing age was associated with a trend towards a higher rate of non-haematological toxicities. Increasing age was associated with higher early treatment discontinuation rates. This is in keeping with post-hoc analysis from the first-line phase 3 AGO-OVAR3 study, which also showed that women 70 years and over experienced comparable rates of toxicity but were more likely to discontinue treatment early [31]. The AGO-OVAR authors in 2007 suggested a potential difference in attitude towards the treatment of older adults. It can be postulated that this difference persists today. It was relatively rare for patients in our study to decline treatment with six patients declining surgery and three declining chemotherapy; however, the more nuanced decision-making over reducing treatment intensity and early treatment cessation is difficult to reliably elucidate retrospectively. A recent study from the Netherlands reported no treatment rates of 16%; in 40% of these cases it was patient choice, and in 29% it was poor condition in the opinion of the physician [32]. The perspectives of older women on treatment intensity, tolerance and treatment goals are worthy of further study, as the reasons for the reduced treatment intensity remain unclear.
4. Materials and Methods
Local study approvals were received from the Royal Marsden NHS Foundation Trust and The Royal United Hospitals Bath NHS Foundation Trust (SE486). This was a retrospective observational evaluation of all women over the aged 65 and over treated consecutively for newly diagnosed epithelial ovarian cancer (including tubal and primary peritoneal) over a 5-year period (December 2009 to August 2015) in two UK NHS Cancer Centres. Standard of care treatment was defined as undergoing cytoreductive surgery at any stage in the primary treatment pathway in combination with platinum-based chemotherapy. Details of treatment received, medical comorbidities, polypharmacy, functional level at baseline (where possible) as well as routinely assessed haematological and biochemical parameters were collected. Where toxicities had not been graded in real-time, according to the description of the event, retrospective grading was applied using CTCAE v4.0 for all grade haematological and grade ≥3 non-haematological toxicities.
The primary objective was to assess the proportion of women over the age of 65 who are offered and receive standard of care first-line management. Secondary objectives included assessment of progression-free and overall survival from first diagnosis and first relapse; proportion of patients who suffered a severe haematological or non-haematological chemotherapy toxicity; proportion of patients who received treatment for relapsed disease; rate of hospitalisation and 30-day mortality during chemotherapy. Patients were considered eligible if they were aged 65 years or older at the time of a first new patient appointment with a histologically or cytologically confirmed diagnosis of epithelial ovarian, primary peritoneal and fallopian tube carcinoma at either institution.
Statistical Considerations
Chi squared test was used to compare patient baseline characteristics and treatment patterns according to age. Progression-free survival was measured from start of treatment to date of progression or death from any cause. Overall survival was defined as the time from date of diagnosis or date of relapse (depending on the endpoint) to death. Patients without an event were censored at last follow up. Data were censored on the 1 August 2016. Survival outcomes were estimated using the Kaplan–Meier method. Hazard ratios for survival, adjusted for factors likely to be of significance such as age, stage and treatment received were calculated using a cox proportional hazards model. All tests are two sided. A p-value of < 0.05 was used to determine statistical significance. All statistical analyses were performed using Stata IC v15.
5. Conclusions
The oldest women continue to receive lower rates of optimal first-line therapy compared to younger women. Once adjusted for FIGO stage, surgical outcome and first-line treatment received, age was no longer an independent risk factor for poorer overall survival. Not receiving standard of care platinum-based chemotherapy and cytoreductive surgery would therefore appear to be a critical factor for the poorer survival outcomes seen in our oldest patients. In the absence of a formal geriatric or frailty assessment, using age alone may lead to inappropriate under-treatment, adversely affecting cancer outcomes in these women. Further assessment of the reasons behind the lower treatment rates in the oldest patients are essential to further understand and were beyond the scope of this retrospective study. Previous work by this group (manuscript under review) has demonstrated that older women desire active treatment and do not consider their age to be a hindrance. A formal frailty or geriatric assessment together with interventions to address issues identified would assist in optimising vulnerable patients. This could improve the rates of treatment delivery and completion in older adults thereby improving outcomes in this key demographic. The prospective UK FAIR-O study (NCT04300699) seeks to address the issue of assessment and management of frailty and medical comorbidities in the general oncology clinic.
Acknowledgments
We acknowledge the contribution of the late Professor Martin Gore CBE who supervised and supported this study.
Author Contributions
Conceptualization: L.D. and S.B.; methodology, L.D., R.B. and S.B.; investigation L.D. and R.B.; data curation, L.D., R.B., J.B. and S.B.; original draft preparation, L.D.; study idea, data acquisition, statistical analysis, preparation of the first draft of the manuscript, writing—review and editing, L.D., R.B., J.B. and S.B. All authors have read and agreed to the published version of the manuscript.
Funding
Lucy Dumas was part-supported by the London Cancer Alliance-Biomedical Research Centre and the Lady Garden Foundation.
Institutional Review Board Statement
Local study approvals were received from the Royal Marsden NHS Foundation Trust and The Royal United Hospitals Bath NHS Foundation Trust (SE486).
Informed Consent Statement
This study was approved as a service evaluation (exempt from patient-level consent) by the Royal Marsden Hospital Committee for Clinical Research.
Data Availability Statement
The data presented here are available on request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 First-line treatment received according to age cohort.
Figure 2 (A) Overall survival according to age cohort. (B) Progression-free survival according to age cohort.
cancers-13-00952-t001_Table 1 Table 1 Patient characteristics: stage and ECOG performance status at baseline.
65–69 Years n = 91 70–74 Years n = 79 75–79 Years n = 53 >80 Years n = 57 Total n = 280 p
n (%) n (%) n (%) n (%) n (%)
FIGO Stage
1 13 (14.3) 4 (5.1) 8 (15.1) 12 (21.1) 37 (13.2) 0.293
2 9 (9.9) 10 (12.7) 3 (5.7) 3 (5.3) 28 (10.0)
3 52 (57.1) 44 (55.7) 33 (62.3) 29 (50.9) 158 (56.4)
4 16 (17.6) 21 (26.6) 6 (11.3) 12 (21.1) 55 (19.6)
Unknown 1 (1.1) 0 0 1 (1.8) 2 (0.7)
ECOG PS
0 30 (33.0) 12 (15.2) 9 (17.0) 5 (8.8) 56 (20.0) 0.008
1 34 (37.4) 38 (48.1) 27 (50.9) 23 (40.4) 122 (43.6)
2 14 (15.4) 18 (22.8) 8 (15.1) 15 (26.3) 55 (19.6)
3 5 (5.5) 9 (11.4) 3 (5.7) 9 (15.8) 26 (9.3)
Unknown 8 (8.8) 2 (2.5) 6 (11.3) 5 (8.8) 21 (7.5)
Histological subtype
High grade serous 62 (68.1) 57 (72.2) 36 (67.9) 40 (70.2) 195 (69.6) 0.547
Low grade serous 3 (3.3) 3 (3.8) 3 (5.7) 3 (5.3) 12 (4.3)
Carcinosarcoma 6 (6.6) 5 (6.3) 4 (7.5) 6 (10.5) 21 (7.5)
Clear cell 8 (8.8) 1 (1.3) 2 (3.8) 1 (1.8) 12 (4.3)
Endometrioid 7 (7.7) 3 (3.8) 2 (3.8) 2 (3.5) 14 (5.0)
Mucinous 1 (1.1) 2 (2.5) 0 0 3 (1.1)
Adenocarcinoma/Mixed/ Undifferentiated 4 (4.4) 8 (10.1) 6 (11.3) 5 (8.8) 23 (8.2)
cancers-13-00952-t002_Table 2 Table 2 Patient characteristics. Medical comorbidities and functional status at baseline.
65–69 Years n = 91 70–74 Years n = 79 75–79 Years n = 53 >80 Years n = 57 Total n = 280 p
n (%) n (%) n (%) n (%) n (%)
Medical comorbidities
Cardiovascular disease 26 (28.6) 21 (26.6) 16 (30.2) 14 (24.6) 77 (27.5) 0.907
Hypertension 37 (40.7) 28 (35.4) 22 (41.5) 26 (45.6) 113 (40.4) 0.650
Previous malignancy 5 (5.5) 4 (5.1) 6 (11.3) 1 (1.8) 16 (5.7) 0.183
Endocrine disease 7 (7.7) 5 (6.3) 5 (9.4) 3 (5.3) 20 (7.1) 0.834
Osteoarthritis 4 (4.4) 5 (6.3) 7 (13.2) 4 (7.0) 20 (7.1) 0.252
Rheumatological disease 2 (2.2) 7 (8.9) 2 (3.8) 1 (1.8) 12 (4.3) 0.122
CVA/MI/CAD 7 (7.7) 4 (5.1) 6 (11.3) 3 (5.3) 20 (7.1) 0.512
Haematological disease 0 2 (2.5) 0 0 2 (0.7) 0.167
Previous DVT 15 (16.5) 8 (10.1) 8 (15.1) 4 (7.0) 35 (12.5) 0.345
Polypharmacy (>3 meds) 31 (34.1) 27 (34.2) 23 (43.4) 30 (52.6) 111 (39.6) 0.010
Respiratory disease 6 (6.6) 15 (19.0) 6 (11.3) 1 (1.8) 28 (10.0) 0.007
Diabetes 9 (9.9) 7 (8.9) 6 (11.3) 7 (12.3) 29 (10.4) 0.850
Cognitive impairment 0 2 (2.5) 0 6 (10.5) 8 (2.9) 0.001
Depression 6 (6.6) 4 (5.1) 0 1 (1.8) 11 (3.9) 0.193
Functional baseline
Lives alone 20 (22.0) 31 (39.2) 18 (34.0) 29 (50.9) 98 (35.0) 0.000
Lives in supported accommodation 0 1 (1.3) 2 (3.8) 4 (7.0) 7 (2.5) 0.032
Use of walking aids 7 (7.7) 12 (15.2) 11 (20.8) 14 (24.6) 44 (15.7) 0.026
Reduced activities of daily living 16 (17.6) 22 (27.9) 13 (24.5) 19 (33.3) 70 (25.0) 0.226
Assistance with activities of daily living 7 (7.7) 10 (12.7) 8 (15.1) 10 (17.5) 35 (12.5) 0.441
History of delirium in last 12 months 0 0 0 3 (5.3) 3 (1.1) 0.007
Cognitive impairment 0 2 (2.5) 0 6 (10.5) 8 (2.9) 0.001
Weight loss in last 3 months 22 (24.2) 22 (27.9) 11 (20.8) 11 (19.3) 66 (23.6) 0.799
Visual impairment 3 (3.3) 1 (1.3) 2 (3.8) 9 (15.8) 15 (5.4) 0.016
Hearing impairment 1 (1.1) 0 2 (3.8) 3 (5.3) 6 (2.1) 0.242
History of falls in last 12 months 1 (1.1) 0 1 (1.9) 3 (5.3) 5 (1.8) 0.106
cancers-13-00952-t003_Table 3 Table 3 Treatment tolerance.
65–69 Years
n = 82 70–74 Years
n = 72 75–70 Years
n = 48 >80 Years
n = 39 Total
n = 241 p-Value
% % % % %
Dose modification at baseline 9.8 12.5 6.3 17.5 11.6 0.365
Dose modification during chemotherapy 29.3 30.6 52.1 37.5 35.5 0.193
Completed 6 cycles of chemotherapy 86.6 86.1 77.1 65.0 82.2 0.034
≥ G2 Haematological toxicity 29.3 19.4 33.3 30.0 27.3 0.554
≥ G3 Non-haematological toxicity 13.4 19.4 27.1 32.5 21.1 0.082
Febrile neutropenia 4.9 2.8 2.1 0.00 2.9 0.540
Hospital admission during chemotherapy 20.7 34.7 25.0 37.5 28.5 0.135
Death within 30 days of chemotherapy 1.2 0.00 4.2 0.00 1.2 0.184
cancers-13-00952-t004_Table 4 Table 4 Univariate and multivariate analysis of factors associated with poorer overall survival.
Univariate Multivariate
n HR 95% CI p HR 95% CI p
Age Cohort 65–69 91 - - - - - -
70–74 79 1.40 (0.96–2.05) 0.081 0.95 (0.60–1.52) 0.833
75–79 53 1.07 (0.68–1.68) 0.772 0.79 (0.44–1.43) 0.441
>80 57 2.20 (1.47–3.27) 0.000 1.76 (1.03–3.02) 0.04
FIGO Stage 1 37 - - -
2 28 1.30 (0.55–3.07) 0.553 7.91 (0.98–63.61) 0.052
3 158 3.69 (1.98–6.89) 0.000 12.99 (1.77–95.20) 0.012
4 55 6.00 (3.08–11.68) 0.000 16.16 (2.11–123.61) 0.007
ECOG PS 0 56 - - -
1 122 1.86 (1.18–2.93) 0.007 2.14 (1.21–3.79) 0.009
2 55 4.02 (2.47–6.53) 0.000 2.53 (1.20–5.35) 0.015
3 26 7.36 (4.13–13.13) 0.000 3.51 (1.37–8.99) 0.009
Cardiovascular disease 77 1.38 (1.01–1.90) 0.043 0.99 (0.62–1.57) 0.95
Taking 3 or more medications 111 0.07 (0.01–0.55) 0.011 1.12 (0.72–1.74) 0.62
Osteoarthritis 16 1.70 (0.96–3.01) 0.070 1.62 (0.76–3.44) 0.209
Reduced activities of daily living 70 2.89 (2.10–3.98) 0.000 1.53 (0.90–2.62) 0.118
History of depression 11 1.86 (0.95–3.65) 0.071 1.89 (0.83–4.30) 0.128
History of weight loss 66 1.51 (1.09–2.11) 0.015 0.93 (0.59–1.47) 0.754
Albumin <35 g/L 114 2.09 (1.56–2.81) 0.000 1.52 (0.97–2.38) 0.065
Haemoglobin <120 g/L 141 1.28 (0.9601.72) 0.093 0.80 (0.53–1.23) 0.311
GFR <60 mL/min 104 1.33 (0.98–1.79) 0.064 1.11 (0.74–1.68) 0.607
cancers-13-00952-t005_Table 5 Table 5 Univariate and multivariate factors associated with poorer overall survival.
Univariate Multivariate
HR 95% CI p HR 95% CI p
Age Cohort 65–69 years - - - - - -
70–74 years 1.40 (0.96–2.05) 0.081 1.22 (0.77–1.95) 0.386
75–79 years 1.07 (0.68–1.68) 0.772 0.85 (0.46–1.54) 0.582
>80 years 2.20 (1.47–3.27) 0.000 0.81 (0.40–1.61) 0.541
FIGO stage 1 - - -
2 1.30 (0.55–3.07) 0.553 2.39 (0.86–6.64) 0.094
3 3.69 (1.98–6.89) 0.000 4.38 (2.02–9.52) 0.000
4 6.00 (3.08–11.68) 0.000 6.96 (2.81–17.24) 0.000
Surgical outcome Residual disease 2.71 (1.82–4.03) 0.000 2.09 (1.32–3.30) 0.002
Platinum- combination - - - - - -
Chemotherapy Single-agent carboplatin 1.29 (0.93–1.77) 0.123 1.34 (0.85–2.17) 0.203
No chemotherapy 2.19 (1.43–3.35) 0.000 4.49 (1.99–10.13) 0.000
Completed 6 cycles 0.34 (0.23–0.49) 0.000 0.33 (0.19–0.59) 0.000
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | Under-Treatment of Older Patients with Newly Diagnosed Epithelial Ovarian Cancer Remains an Issue.
Older women with ovarian cancer have disproportionately poorer survival outcomes than their younger counterparts and receive less treatment. In order to understand where the gaps lie in the treatment of older patients, studies incorporating more detailed assessment of baseline characteristics and treatment delivery beyond the scope of most cancer registries are required. We aimed to assess the proportion of women over the age of 65 who are offered and receive standard of care for first-line ovarian cancer at two UK NHS Cancer Centres over a 5-year period (December 2009 to August 2015). Standard of care treatment was defined as a combination of cytoreductive surgery and if indicated platinum-based chemotherapy (combination or single-agent). Sixty-five percent of patients aged 65 and above received standard of care treatment. Increasing age was associated with lower rates of receiving standard of care (35% > 80 years old versus 78% of 65-69-year-olds, p = 0.000). Older women were less likely to complete the planned chemotherapy course (p = 0.034). The oldest women continue to receive lower rates of standard care compared to younger women. Once adjusted for Federation of Gynaecology and Obstetrics (FIGO) stage, Eastern Cooperative Oncology Group (ECOG) performance status and first-line treatment received, age was no longer an independent risk factor for poorer overall survival. Optimisation of vulnerable patients utilising a comprehensive geriatric assessment and directed interventions to facilitate the delivery of standard of care treatment could help narrow the survival discrepancy between the oldest patients and their younger counterparts.
1. Introduction
Ovarian cancer (including primary peritoneal and fallopian tube cancer) is predominantly diagnosed in older women with around half of all new diagnoses occurring in women over the age of 65. Older patients are less likely to be enrolled in clinical trials [1,2] that go onto to shape current gold standards. Treatment decisions are usually based on clinical trial results, which include a younger, less frail population and are applied to an older and often less well group. The efficacy and tolerability of standard of care and novel therapies in an older, potentially frailer population are therefore not clearly understood.
It has long been shown that survival outcomes are disproportionately lower in older patients [3] and delayed diagnosis/late presentation [4], more advanced disease at diagnosis [5,6,7], higher rates of emergency presentation [8], higher rates of unclassified or unclassifiable tumours [3] as well as lower physical performance status and higher prevalence of medical and functional comorbidities [9] contribute to this. Recent studies have reported high rates of no recorded treatment in older patients, for example 60% of ovarian cancer patients aged over 79 had no record of any treatment in England between 2016 and 2018 [10,11]. Developing our understanding of the “real-world” experience of treatment for ovarian cancer in an older population is necessary. Until the reasons for the difference in survival between older and younger women are more clearly understood, efforts to address the gaps and improve outcomes in our older population will be hampered. Large-scale cancer registry data by both the EUROCARE [12,13,14,15] series and the International Cancer Benchmarking Partnership (ICBP) [6,7,16,17] demonstrate that both short and long-term survival outcomes in older women continue to be significantly inferior to those seen in middle-aged and younger women [12,17,18]. Notably, an improving trend in 1- and 5-year survival for all age groups has been reported excepting those aged over 75 years [19].
The field of geriatric oncology has rapidly developed over the last two decades. The core principles outline the need to holistically assess patients using a comprehensive geriatric assessment rather than basing treatment decisions purely on chronological age. Both the International Society of Geriatric Oncology (SIOG) [20] and the American Society of Clinical Oncology (ASCO) [21] have now recommended that geriatric assessment (GA) be undertaken in all adults aged 65 years and over being considered for systemic anti-cancer therapy. Crucially, clinicians should implement GA-directed interventions in order to optimise patient care.
2. Results
2.1. Patient Baseline Characteristics
Two hundred and eighty patients met the inclusion criteria. Patients were divided into four age cohorts (65–69 years, 70–74 years, 75–79 years and >80 years). The majority (76%) of patients had stage 3 or 4 disease at presentation (Table 1). Stage distribution did not alter with increasing age (p = 0.293). 29% of patients were ECOG performance status 2 or 3. Increasing age was significantly associated with a worsening ECOG performance status (p = 0.008). Forty-nine percent of patients over the age of 80 were PS 0 or 1 compared to 70.4% of patients in the 65–69 years cohort (Table 1). The majority (69.6%) of patients were diagnosed with high-grade serous carcinoma. Histological subtype did not vary according to age (p = 0.547).
The most commonly documented comorbidities were cardiovascular disease (27.5%), hypertension (40.4%), respiratory disease (10%) and diabetes (10.4%). Polypharmacy at the initial consultation, defined as taking 3 or more daily prescribed medications, was present in 40% of patients. Neither cardiovascular disease nor hypertension was associated with increasing age. 48.9% women were anaemic (any grade) at baseline with 11.4% patients having a Grade 2 or higher anaemia. Impaired renal function at the start of treatment was also common with 37% of all patients having at least a mild-moderate reduction of glomerular-filtration rate (GFR) of 60 mL/min or less, amounting to chronic kidney disease grade 3. A total of 40.7% patients had an albumin below 35 g/L at baseline and 22.5% of patients had an albumin less than 30 g/L. Hypoalbuminaemia was not associated with increasing age (p = 0.36) (Table 2). Factors and comorbidities significantly associated with advancing age were polypharmacy (p = 0.01), respiratory disease (p = 0.007) and cognitive impairment (p = 0.001) (Table 2.) Increasing age was associated with a higher proportion of women living alone (51% of those >80 years compared with 22% of those aged 65–69 years, p = 0.000). Older women were also significantly more likely to live in supported accommodation (p = 0.032), use a walking aid (p = 0.026) or have a degree of visual impairment (p = 0.016). A quarter of all patients reported reduced activities of daily living in the weeks and months preceding their diagnosis. Self-reported weight loss was also prevalent with 23.6% of patients reporting weight loss over the 3 months prior to their diagnosis (Table 2.)
2.2. First Line Treatment
Sixty-five percent of patients received standard of care cytoreductive surgery and platinum-based chemotherapy in keeping with the European Society of Medical Oncolgogy ESMO)-European-Society of Gynaecological Oncology (ESGO) consensus recommendations [22]. Increasing age was associated with reducing rates of receiving standard of care therapy with 35.1% of those over the age of 80 receiving both chemotherapy and surgery compared to 78% in those aged 65–69 years (p = 0.000). Ten percent of patients over the age of 80 received no cancer treatment (Figure 1). Six (2%) patients declined surgery and three (1%) declined chemotherapy. Increasing age was associated with lower rates of undergoing cytoreductive surgery (p = 0.001) as well as complete cytoreduction (defined according to the post-operative report) (p = 0.006) with complete cytoreduction obtained in only 28% of those over the age of 80 compared to 69% in those aged 65–69. When optimal cytoreduction (<1 cm residual disease) is reported as a proportion of those patients who underwent surgery, the rates of optimal cytoreduction was 76% in all age cohorts apart from those over 80 where it was 49%. 53.7% of women received standard carboplatin and paclitaxel chemotherapy as first-line treatment. Older women were less likely to receive doublet chemotherapy (19.3% in those over the age of 80 compared to 73.6% in those aged 65–69 years, p = 0.000). Overall, 7.8% women aged 65 and above any form of targeted therapy during first-line treatment. This proportion decreased with advancing age (2.3% of women over the age of 80 compared to 12.4% women between the ages of 65–69 received some form of targeted therapy during first-line treatment (p = 0.05).
Subsequently, the primary treatment of only those women with advanced (Federation of Gynaecology and Obstetrics (FIGO) stage III/IV) disease was assessed. A total of 62.9% of women aged 65 and over received standard of care, with this proportion decreasing significantly with increasing age (p = 0.000). 46.3% of women aged 80 years and over underwent cytoreductive surgery. In these women complete cytoreduction was achieved in 31.6%, compared to those aged between 65–69 years of whom 82.4% underwent surgery, and 69.6% had complete cytoreduction (p = 0.014).
2.3. Treatment Tolerance
Overall, 27.3% of patients developed a grade two or higher haematological toxicity. Neutropenia was more common in younger patients (69.6% in those aged 65–69 vs. 18.8% in those aged 75–79, p = 0.007). Older patients did not experience higher rates of severe haematological toxicity (p = 0.554). However, increasing age was associated with a trend towards a higher rate of G3 or 4 non-haematological toxicities although this did not reach statistical significance (32.5% vs. 13.4% in those aged >80 years vs. those aged 65–69 years, p = 0.082). Increasing age was significantly associated with a lower likelihood of completing 6 cycles (p = 0.034). Of the 38 (15.8%) women who discontinued treatment early, 21 (55%) did so because of toxicity. Discontinuation due to toxicity was higher in older patients, for example 54.5% of 75–79-year-olds compared to 36.4% of those aged 65–69 years, although this did not reach statistical significance (p = 0.15). 28.5% of all patients were admitted to hospital as an emergency at some stage during their primary treatment with no variation due to age (p = 0.135), 30-day mortality was 1.24% across the whole cohort and did not vary according to age (p = 0.184) (Table 3).
2.4. Treatment at Relapse
At first relapse, 50.4% of women received chemotherapy; however, older women were significantly less likely to receive second-line chemotherapy at progression. A total of 35.5% of women over the age of 75 received chemotherapy at relapse, compared to 62.5% of those aged 65–69 years (p = 0.021). One patient (aged 75 years) underwent secondary debulking surgery. Seventy-five women (59% of those who had treatment for relapsed disease) received carboplatin-based chemotherapy at first relapse. Of those who received chemotherapy at first relapse, 56 (45%) received a carboplatin doublet regimen (paclitaxel, pegylated liposomal doxorubicin or gemcitabine with or without a targeted agent for example, bevacizumab). Nineteen (15%) women received single-agent carboplatin. Of those who received platinum at first relapse, 65% achieved some degree of tumour shrinkage as their best response according to the local radiological report with 89% achieving at least stable disease. In those patients who received non-platinum containing regimens, 21 patients (15%) received weekly paclitaxel resulting in a 33.3% radiological response rate and a 52% clinical benefit rate (defined as patients who achieved at least stable disease as their best response documented). Twenty-three (18.9%) patients received either pegylated liposomal doxorubicin or doxorubicin. No responses were seen in this group although 6 (26%) patients had stabilisation of their disease.
2.5. Survival Outcomes
Median overall survival (OS) for all patients was 31.5 months. For patients diagnosed with stage III and stage IV disease, median OS was 28.3 and 14 months respectively. 1-year and 5-year survival was 78.1% (95% CI 72.7–82.5) and 28.7% (95% CI 22.5–35.2) respectively. Overall survival was broadly equivalent over the first three age cohorts however patients over the age of 80 had a significantly lower survival than those aged 65–69 years (median OS 20.02 months vs. 44.91 months, p = 0.000) (Figure 2). First line carboplatin/paclitaxel combination chemotherapy was associated with improved survival outcomes compared to single-agent carboplatin (OS 39.5 vs. 30.6 months), those patients who received no chemotherapy had an OS of 9.7 months (p = 0.003). Progression-free survival (PFS) was similar across all age groups up to the age of 80 but patients aged 80 years and over had a median PFS of 12.3 months compared to 16.4 in those aged 65–69 years (HR 2.0 p = 0.00) (Figure 2).
In univariate analysis, age over 80 years at diagnosis, FIGO stage III/IV disease, incomplete cytoreduction and an ECOG PS of greater than 1 were all associated with poorer survival outcomes. Of the baseline factors and comorbidities collected, the presence of cardiovascular disease (p = 0.043), polypharmacy (p = 0.011) or having a current or past history of smoking (p = 0.008) were all associated with poorer survival outcomes. Requiring assistance with activities of daily living (ADL) (p = 0.000), reporting reduced ADLS (p = 0.000) and weight loss at diagnosis (p = 0.015) were associated with poorer survival outcomes (Table 4). Of the biochemical parameters collected, having any degree of hypoalbuminaemia (p = 0.000) or baseline haemoglobin of less than 110 g/L (p = 0.000) were associated with poorer survival outcomes. GFR was associated with poorer survival as a continuous variable (p = 0.036) however using a threshold of a GFR of 60 mL/min (CKD 3) was not associated with poorer survival outcomes (p = 0.064) (Table 4).
A cox proportional hazards multivariate model was built including treatment-related factors that were predictive, by univariate analysis for overall survival. When adjusted for FIGO stage, surgical outcome, chemotherapy treatment and completion of chemotherapy, age over 80-years-old was no longer an independent risk factor for poorer overall survival. Completion of chemotherapy remained independently associated with overall survival where single-agent versus platinum-doublet chemotherapy was not associated with a significantly different in overall survival in either univariate or multivariate analysis (Table 5).
3. Discussion
This study provides a useful insight into the current real-world treatment of older women diagnosed with epithelial ovarian cancer in two UK cancer centres. There were very low rates of unclassifiable tumours in this series compared to national cancer registry data where over 50% of women over the age of 80 had an unclassified epithelial or miscellaneous tumour [3]. The lack of relationship between unclassifiable tumours and increasing age suggests either an improvement in the approach to the diagnostic process in older patients with more women having a true histological diagnosis being pursued, or the importance of cancer centre management of presumed ovarian cancer. Delayed time to diagnosis and therefore later stage at diagnosis has also been postulated as a cause for poorer survival rates however, stage distribution also did not vary with age in this population with the majority of women of all ages being diagnosed with stage 3 and 4 disease.
In this series, older patients were more likely to have a poorer ECOG performance status however it is well recognised that ECOG performance status alone is a crude measure in an elderly population that does not accurately reflect the functional and comorbid status of older patients [23,24] and it has also been previously shown that poor performance status should not necessarily preclude first-line treatment in epithelial ovarian cancer due to the high response rates observed to platinum-based chemotherapy [25]. Although many older women maintain fit and active lives, a quarter of the study population reported reduced activities of daily living in the preceding weeks and months before their diagnosis. A significant proportion of women in this study also reported living alone, whilst not a concern in and of itself, living alone without sufficient social network or community support particularly in the context of frailty is a challenge for both patients and oncologists when systemic anti-cancer therapy is being considered.
The most striking difference between the oldest patients and those younger than 80 years was that seen in primary treatment received. Under-treatment has long been postulated as one of the primary reasons for the poorer outcomes in older patients. A large retrospective study in France assessed the impact of age on treatment and survival outcomes whether or not guideline-recommendations for therapy were followed between 1997 and 2011. Women 70 years and over compared to those younger were less likely to undergo surgery (60.9% versus 89.6%, p < 0.0001) or receive chemotherapy (57.4% versus 76.4%, p < 0.0001). Only 31.9% of patients 70 years and over underwent both surgery and chemotherapy [26]. A prospective study (OVCAD) that included 275 women treated for primary ovarian cancer between 2005 and 2008 also showed that older women were less likely to receive optimal therapy and had poorer progression-free and overall survival. In multivariate analysis, age was an independent risk factor for poorer overall but not progression-free survival [27]. Our findings confirm that older women continue to receive less treatment than their younger and middle-aged counterparts and this is likely to be a significant factor in explaining the poorer outcomes seen in this population. A limitation of this work is that it was not possible from this retrospective study to ascertain whether, in those patients who did not receive either surgery or chemotherapy whether this decision was patient or clinician-led. Documentation of the rationale for a decision for not treatment should be consistently recorded in patient records. In addition, interview studies of the multidisciplinary team making treatment decisions may shed more light on the rationale for patients not receiving standard of care. It has previously been shown that older women desire cure as much as their younger counterparts and are more willing to undergo potentially disfiguring surgery to achieve this than younger patients [28]. In work also undertaken by our group (manuscript under review), we report that older patients desired active treatment and did not consider their age to be a hindrance.
The difference in survival for the oldest patients becoming no longer statistically significant once FIGO stage, surgical outcome and crucially, chemotherapy received are incorporated into the model provides further evidence that if even the oldest patients receive optimal therapy, survival outcomes are comparable. It has been shown that medical and social optimisation of older patients prior to and during systemic anti-cancer therapy can improve chemotherapy completion rates [29]. This approach is being tested in a wider scale in both the PREPARE [30] and GIVE (NCT02785887) studies; these potentially practice-changing results are awaited. We report here that older patients were less likely to receive targeted therapy, however, the only targeted therapy available during the study period was bevacizumab, which only received NICE approval in 2013 (i.e., the final two years of the study period) and thus these rates may not be fully representative.
Haematological toxicity rates were comparable across the age groups however increasing age was associated with a trend towards a higher rate of non-haematological toxicities. Increasing age was associated with higher early treatment discontinuation rates. This is in keeping with post-hoc analysis from the first-line phase 3 AGO-OVAR3 study, which also showed that women 70 years and over experienced comparable rates of toxicity but were more likely to discontinue treatment early [31]. The AGO-OVAR authors in 2007 suggested a potential difference in attitude towards the treatment of older adults. It can be postulated that this difference persists today. It was relatively rare for patients in our study to decline treatment with six patients declining surgery and three declining chemotherapy; however, the more nuanced decision-making over reducing treatment intensity and early treatment cessation is difficult to reliably elucidate retrospectively. A recent study from the Netherlands reported no treatment rates of 16%; in 40% of these cases it was patient choice, and in 29% it was poor condition in the opinion of the physician [32]. The perspectives of older women on treatment intensity, tolerance and treatment goals are worthy of further study, as the reasons for the reduced treatment intensity remain unclear.
4. Materials and Methods
Local study approvals were received from the Royal Marsden NHS Foundation Trust and The Royal United Hospitals Bath NHS Foundation Trust (SE486). This was a retrospective observational evaluation of all women over the aged 65 and over treated consecutively for newly diagnosed epithelial ovarian cancer (including tubal and primary peritoneal) over a 5-year period (December 2009 to August 2015) in two UK NHS Cancer Centres. Standard of care treatment was defined as undergoing cytoreductive surgery at any stage in the primary treatment pathway in combination with platinum-based chemotherapy. Details of treatment received, medical comorbidities, polypharmacy, functional level at baseline (where possible) as well as routinely assessed haematological and biochemical parameters were collected. Where toxicities had not been graded in real-time, according to the description of the event, retrospective grading was applied using CTCAE v4.0 for all grade haematological and grade ≥3 non-haematological toxicities.
The primary objective was to assess the proportion of women over the age of 65 who are offered and receive standard of care first-line management. Secondary objectives included assessment of progression-free and overall survival from first diagnosis and first relapse; proportion of patients who suffered a severe haematological or non-haematological chemotherapy toxicity; proportion of patients who received treatment for relapsed disease; rate of hospitalisation and 30-day mortality during chemotherapy. Patients were considered eligible if they were aged 65 years or older at the time of a first new patient appointment with a histologically or cytologically confirmed diagnosis of epithelial ovarian, primary peritoneal and fallopian tube carcinoma at either institution.
Statistical Considerations
Chi squared test was used to compare patient baseline characteristics and treatment patterns according to age. Progression-free survival was measured from start of treatment to date of progression or death from any cause. Overall survival was defined as the time from date of diagnosis or date of relapse (depending on the endpoint) to death. Patients without an event were censored at last follow up. Data were censored on the 1 August 2016. Survival outcomes were estimated using the Kaplan–Meier method. Hazard ratios for survival, adjusted for factors likely to be of significance such as age, stage and treatment received were calculated using a cox proportional hazards model. All tests are two sided. A p-value of < 0.05 was used to determine statistical significance. All statistical analyses were performed using Stata IC v15.
5. Conclusions
The oldest women continue to receive lower rates of optimal first-line therapy compared to younger women. Once adjusted for FIGO stage, surgical outcome and first-line treatment received, age was no longer an independent risk factor for poorer overall survival. Not receiving standard of care platinum-based chemotherapy and cytoreductive surgery would therefore appear to be a critical factor for the poorer survival outcomes seen in our oldest patients. In the absence of a formal geriatric or frailty assessment, using age alone may lead to inappropriate under-treatment, adversely affecting cancer outcomes in these women. Further assessment of the reasons behind the lower treatment rates in the oldest patients are essential to further understand and were beyond the scope of this retrospective study. Previous work by this group (manuscript under review) has demonstrated that older women desire active treatment and do not consider their age to be a hindrance. A formal frailty or geriatric assessment together with interventions to address issues identified would assist in optimising vulnerable patients. This could improve the rates of treatment delivery and completion in older adults thereby improving outcomes in this key demographic. The prospective UK FAIR-O study (NCT04300699) seeks to address the issue of assessment and management of frailty and medical comorbidities in the general oncology clinic.
Acknowledgments
We acknowledge the contribution of the late Professor Martin Gore CBE who supervised and supported this study.
Author Contributions
Conceptualization: L.D. and S.B.; methodology, L.D., R.B. and S.B.; investigation L.D. and R.B.; data curation, L.D., R.B., J.B. and S.B.; original draft preparation, L.D.; study idea, data acquisition, statistical analysis, preparation of the first draft of the manuscript, writing—review and editing, L.D., R.B., J.B. and S.B. All authors have read and agreed to the published version of the manuscript.
Funding
Lucy Dumas was part-supported by the London Cancer Alliance-Biomedical Research Centre and the Lady Garden Foundation.
Institutional Review Board Statement
Local study approvals were received from the Royal Marsden NHS Foundation Trust and The Royal United Hospitals Bath NHS Foundation Trust (SE486).
Informed Consent Statement
This study was approved as a service evaluation (exempt from patient-level consent) by the Royal Marsden Hospital Committee for Clinical Research.
Data Availability Statement
The data presented here are available on request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 First-line treatment received according to age cohort.
Figure 2 (A) Overall survival according to age cohort. (B) Progression-free survival according to age cohort.
cancers-13-00952-t001_Table 1 Table 1 Patient characteristics: stage and ECOG performance status at baseline.
65–69 Years n = 91 70–74 Years n = 79 75–79 Years n = 53 >80 Years n = 57 Total n = 280 p
n (%) n (%) n (%) n (%) n (%)
FIGO Stage
1 13 (14.3) 4 (5.1) 8 (15.1) 12 (21.1) 37 (13.2) 0.293
2 9 (9.9) 10 (12.7) 3 (5.7) 3 (5.3) 28 (10.0)
3 52 (57.1) 44 (55.7) 33 (62.3) 29 (50.9) 158 (56.4)
4 16 (17.6) 21 (26.6) 6 (11.3) 12 (21.1) 55 (19.6)
Unknown 1 (1.1) 0 0 1 (1.8) 2 (0.7)
ECOG PS
0 30 (33.0) 12 (15.2) 9 (17.0) 5 (8.8) 56 (20.0) 0.008
1 34 (37.4) 38 (48.1) 27 (50.9) 23 (40.4) 122 (43.6)
2 14 (15.4) 18 (22.8) 8 (15.1) 15 (26.3) 55 (19.6)
3 5 (5.5) 9 (11.4) 3 (5.7) 9 (15.8) 26 (9.3)
Unknown 8 (8.8) 2 (2.5) 6 (11.3) 5 (8.8) 21 (7.5)
Histological subtype
High grade serous 62 (68.1) 57 (72.2) 36 (67.9) 40 (70.2) 195 (69.6) 0.547
Low grade serous 3 (3.3) 3 (3.8) 3 (5.7) 3 (5.3) 12 (4.3)
Carcinosarcoma 6 (6.6) 5 (6.3) 4 (7.5) 6 (10.5) 21 (7.5)
Clear cell 8 (8.8) 1 (1.3) 2 (3.8) 1 (1.8) 12 (4.3)
Endometrioid 7 (7.7) 3 (3.8) 2 (3.8) 2 (3.5) 14 (5.0)
Mucinous 1 (1.1) 2 (2.5) 0 0 3 (1.1)
Adenocarcinoma/Mixed/ Undifferentiated 4 (4.4) 8 (10.1) 6 (11.3) 5 (8.8) 23 (8.2)
cancers-13-00952-t002_Table 2 Table 2 Patient characteristics. Medical comorbidities and functional status at baseline.
65–69 Years n = 91 70–74 Years n = 79 75–79 Years n = 53 >80 Years n = 57 Total n = 280 p
n (%) n (%) n (%) n (%) n (%)
Medical comorbidities
Cardiovascular disease 26 (28.6) 21 (26.6) 16 (30.2) 14 (24.6) 77 (27.5) 0.907
Hypertension 37 (40.7) 28 (35.4) 22 (41.5) 26 (45.6) 113 (40.4) 0.650
Previous malignancy 5 (5.5) 4 (5.1) 6 (11.3) 1 (1.8) 16 (5.7) 0.183
Endocrine disease 7 (7.7) 5 (6.3) 5 (9.4) 3 (5.3) 20 (7.1) 0.834
Osteoarthritis 4 (4.4) 5 (6.3) 7 (13.2) 4 (7.0) 20 (7.1) 0.252
Rheumatological disease 2 (2.2) 7 (8.9) 2 (3.8) 1 (1.8) 12 (4.3) 0.122
CVA/MI/CAD 7 (7.7) 4 (5.1) 6 (11.3) 3 (5.3) 20 (7.1) 0.512
Haematological disease 0 2 (2.5) 0 0 2 (0.7) 0.167
Previous DVT 15 (16.5) 8 (10.1) 8 (15.1) 4 (7.0) 35 (12.5) 0.345
Polypharmacy (>3 meds) 31 (34.1) 27 (34.2) 23 (43.4) 30 (52.6) 111 (39.6) 0.010
Respiratory disease 6 (6.6) 15 (19.0) 6 (11.3) 1 (1.8) 28 (10.0) 0.007
Diabetes 9 (9.9) 7 (8.9) 6 (11.3) 7 (12.3) 29 (10.4) 0.850
Cognitive impairment 0 2 (2.5) 0 6 (10.5) 8 (2.9) 0.001
Depression 6 (6.6) 4 (5.1) 0 1 (1.8) 11 (3.9) 0.193
Functional baseline
Lives alone 20 (22.0) 31 (39.2) 18 (34.0) 29 (50.9) 98 (35.0) 0.000
Lives in supported accommodation 0 1 (1.3) 2 (3.8) 4 (7.0) 7 (2.5) 0.032
Use of walking aids 7 (7.7) 12 (15.2) 11 (20.8) 14 (24.6) 44 (15.7) 0.026
Reduced activities of daily living 16 (17.6) 22 (27.9) 13 (24.5) 19 (33.3) 70 (25.0) 0.226
Assistance with activities of daily living 7 (7.7) 10 (12.7) 8 (15.1) 10 (17.5) 35 (12.5) 0.441
History of delirium in last 12 months 0 0 0 3 (5.3) 3 (1.1) 0.007
Cognitive impairment 0 2 (2.5) 0 6 (10.5) 8 (2.9) 0.001
Weight loss in last 3 months 22 (24.2) 22 (27.9) 11 (20.8) 11 (19.3) 66 (23.6) 0.799
Visual impairment 3 (3.3) 1 (1.3) 2 (3.8) 9 (15.8) 15 (5.4) 0.016
Hearing impairment 1 (1.1) 0 2 (3.8) 3 (5.3) 6 (2.1) 0.242
History of falls in last 12 months 1 (1.1) 0 1 (1.9) 3 (5.3) 5 (1.8) 0.106
cancers-13-00952-t003_Table 3 Table 3 Treatment tolerance.
65–69 Years
n = 82 70–74 Years
n = 72 75–70 Years
n = 48 >80 Years
n = 39 Total
n = 241 p-Value
% % % % %
Dose modification at baseline 9.8 12.5 6.3 17.5 11.6 0.365
Dose modification during chemotherapy 29.3 30.6 52.1 37.5 35.5 0.193
Completed 6 cycles of chemotherapy 86.6 86.1 77.1 65.0 82.2 0.034
≥ G2 Haematological toxicity 29.3 19.4 33.3 30.0 27.3 0.554
≥ G3 Non-haematological toxicity 13.4 19.4 27.1 32.5 21.1 0.082
Febrile neutropenia 4.9 2.8 2.1 0.00 2.9 0.540
Hospital admission during chemotherapy 20.7 34.7 25.0 37.5 28.5 0.135
Death within 30 days of chemotherapy 1.2 0.00 4.2 0.00 1.2 0.184
cancers-13-00952-t004_Table 4 Table 4 Univariate and multivariate analysis of factors associated with poorer overall survival.
Univariate Multivariate
n HR 95% CI p HR 95% CI p
Age Cohort 65–69 91 - - - - - -
70–74 79 1.40 (0.96–2.05) 0.081 0.95 (0.60–1.52) 0.833
75–79 53 1.07 (0.68–1.68) 0.772 0.79 (0.44–1.43) 0.441
>80 57 2.20 (1.47–3.27) 0.000 1.76 (1.03–3.02) 0.04
FIGO Stage 1 37 - - -
2 28 1.30 (0.55–3.07) 0.553 7.91 (0.98–63.61) 0.052
3 158 3.69 (1.98–6.89) 0.000 12.99 (1.77–95.20) 0.012
4 55 6.00 (3.08–11.68) 0.000 16.16 (2.11–123.61) 0.007
ECOG PS 0 56 - - -
1 122 1.86 (1.18–2.93) 0.007 2.14 (1.21–3.79) 0.009
2 55 4.02 (2.47–6.53) 0.000 2.53 (1.20–5.35) 0.015
3 26 7.36 (4.13–13.13) 0.000 3.51 (1.37–8.99) 0.009
Cardiovascular disease 77 1.38 (1.01–1.90) 0.043 0.99 (0.62–1.57) 0.95
Taking 3 or more medications 111 0.07 (0.01–0.55) 0.011 1.12 (0.72–1.74) 0.62
Osteoarthritis 16 1.70 (0.96–3.01) 0.070 1.62 (0.76–3.44) 0.209
Reduced activities of daily living 70 2.89 (2.10–3.98) 0.000 1.53 (0.90–2.62) 0.118
History of depression 11 1.86 (0.95–3.65) 0.071 1.89 (0.83–4.30) 0.128
History of weight loss 66 1.51 (1.09–2.11) 0.015 0.93 (0.59–1.47) 0.754
Albumin <35 g/L 114 2.09 (1.56–2.81) 0.000 1.52 (0.97–2.38) 0.065
Haemoglobin <120 g/L 141 1.28 (0.9601.72) 0.093 0.80 (0.53–1.23) 0.311
GFR <60 mL/min 104 1.33 (0.98–1.79) 0.064 1.11 (0.74–1.68) 0.607
cancers-13-00952-t005_Table 5 Table 5 Univariate and multivariate factors associated with poorer overall survival.
Univariate Multivariate
HR 95% CI p HR 95% CI p
Age Cohort 65–69 years - - - - - -
70–74 years 1.40 (0.96–2.05) 0.081 1.22 (0.77–1.95) 0.386
75–79 years 1.07 (0.68–1.68) 0.772 0.85 (0.46–1.54) 0.582
>80 years 2.20 (1.47–3.27) 0.000 0.81 (0.40–1.61) 0.541
FIGO stage 1 - - -
2 1.30 (0.55–3.07) 0.553 2.39 (0.86–6.64) 0.094
3 3.69 (1.98–6.89) 0.000 4.38 (2.02–9.52) 0.000
4 6.00 (3.08–11.68) 0.000 6.96 (2.81–17.24) 0.000
Surgical outcome Residual disease 2.71 (1.82–4.03) 0.000 2.09 (1.32–3.30) 0.002
Platinum- combination - - - - - -
Chemotherapy Single-agent carboplatin 1.29 (0.93–1.77) 0.123 1.34 (0.85–2.17) 0.203
No chemotherapy 2.19 (1.43–3.35) 0.000 4.49 (1.99–10.13) 0.000
Completed 6 cycles 0.34 (0.23–0.49) 0.000 0.33 (0.19–0.59) 0.000
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | Under-Treatment of Older Patients with Newly Diagnosed Epithelial Ovarian Cancer Remains an Issue.
Older women with ovarian cancer have disproportionately poorer survival outcomes than their younger counterparts and receive less treatment. In order to understand where the gaps lie in the treatment of older patients, studies incorporating more detailed assessment of baseline characteristics and treatment delivery beyond the scope of most cancer registries are required. We aimed to assess the proportion of women over the age of 65 who are offered and receive standard of care for first-line ovarian cancer at two UK NHS Cancer Centres over a 5-year period (December 2009 to August 2015). Standard of care treatment was defined as a combination of cytoreductive surgery and if indicated platinum-based chemotherapy (combination or single-agent). Sixty-five percent of patients aged 65 and above received standard of care treatment. Increasing age was associated with lower rates of receiving standard of care (35% > 80 years old versus 78% of 65-69-year-olds, p = 0.000). Older women were less likely to complete the planned chemotherapy course (p = 0.034). The oldest women continue to receive lower rates of standard care compared to younger women. Once adjusted for Federation of Gynaecology and Obstetrics (FIGO) stage, Eastern Cooperative Oncology Group (ECOG) performance status and first-line treatment received, age was no longer an independent risk factor for poorer overall survival. Optimisation of vulnerable patients utilising a comprehensive geriatric assessment and directed interventions to facilitate the delivery of standard of care treatment could help narrow the survival discrepancy between the oldest patients and their younger counterparts.
1. Introduction
Ovarian cancer (including primary peritoneal and fallopian tube cancer) is predominantly diagnosed in older women with around half of all new diagnoses occurring in women over the age of 65. Older patients are less likely to be enrolled in clinical trials [1,2] that go onto to shape current gold standards. Treatment decisions are usually based on clinical trial results, which include a younger, less frail population and are applied to an older and often less well group. The efficacy and tolerability of standard of care and novel therapies in an older, potentially frailer population are therefore not clearly understood.
It has long been shown that survival outcomes are disproportionately lower in older patients [3] and delayed diagnosis/late presentation [4], more advanced disease at diagnosis [5,6,7], higher rates of emergency presentation [8], higher rates of unclassified or unclassifiable tumours [3] as well as lower physical performance status and higher prevalence of medical and functional comorbidities [9] contribute to this. Recent studies have reported high rates of no recorded treatment in older patients, for example 60% of ovarian cancer patients aged over 79 had no record of any treatment in England between 2016 and 2018 [10,11]. Developing our understanding of the “real-world” experience of treatment for ovarian cancer in an older population is necessary. Until the reasons for the difference in survival between older and younger women are more clearly understood, efforts to address the gaps and improve outcomes in our older population will be hampered. Large-scale cancer registry data by both the EUROCARE [12,13,14,15] series and the International Cancer Benchmarking Partnership (ICBP) [6,7,16,17] demonstrate that both short and long-term survival outcomes in older women continue to be significantly inferior to those seen in middle-aged and younger women [12,17,18]. Notably, an improving trend in 1- and 5-year survival for all age groups has been reported excepting those aged over 75 years [19].
The field of geriatric oncology has rapidly developed over the last two decades. The core principles outline the need to holistically assess patients using a comprehensive geriatric assessment rather than basing treatment decisions purely on chronological age. Both the International Society of Geriatric Oncology (SIOG) [20] and the American Society of Clinical Oncology (ASCO) [21] have now recommended that geriatric assessment (GA) be undertaken in all adults aged 65 years and over being considered for systemic anti-cancer therapy. Crucially, clinicians should implement GA-directed interventions in order to optimise patient care.
2. Results
2.1. Patient Baseline Characteristics
Two hundred and eighty patients met the inclusion criteria. Patients were divided into four age cohorts (65–69 years, 70–74 years, 75–79 years and >80 years). The majority (76%) of patients had stage 3 or 4 disease at presentation (Table 1). Stage distribution did not alter with increasing age (p = 0.293). 29% of patients were ECOG performance status 2 or 3. Increasing age was significantly associated with a worsening ECOG performance status (p = 0.008). Forty-nine percent of patients over the age of 80 were PS 0 or 1 compared to 70.4% of patients in the 65–69 years cohort (Table 1). The majority (69.6%) of patients were diagnosed with high-grade serous carcinoma. Histological subtype did not vary according to age (p = 0.547).
The most commonly documented comorbidities were cardiovascular disease (27.5%), hypertension (40.4%), respiratory disease (10%) and diabetes (10.4%). Polypharmacy at the initial consultation, defined as taking 3 or more daily prescribed medications, was present in 40% of patients. Neither cardiovascular disease nor hypertension was associated with increasing age. 48.9% women were anaemic (any grade) at baseline with 11.4% patients having a Grade 2 or higher anaemia. Impaired renal function at the start of treatment was also common with 37% of all patients having at least a mild-moderate reduction of glomerular-filtration rate (GFR) of 60 mL/min or less, amounting to chronic kidney disease grade 3. A total of 40.7% patients had an albumin below 35 g/L at baseline and 22.5% of patients had an albumin less than 30 g/L. Hypoalbuminaemia was not associated with increasing age (p = 0.36) (Table 2). Factors and comorbidities significantly associated with advancing age were polypharmacy (p = 0.01), respiratory disease (p = 0.007) and cognitive impairment (p = 0.001) (Table 2.) Increasing age was associated with a higher proportion of women living alone (51% of those >80 years compared with 22% of those aged 65–69 years, p = 0.000). Older women were also significantly more likely to live in supported accommodation (p = 0.032), use a walking aid (p = 0.026) or have a degree of visual impairment (p = 0.016). A quarter of all patients reported reduced activities of daily living in the weeks and months preceding their diagnosis. Self-reported weight loss was also prevalent with 23.6% of patients reporting weight loss over the 3 months prior to their diagnosis (Table 2.)
2.2. First Line Treatment
Sixty-five percent of patients received standard of care cytoreductive surgery and platinum-based chemotherapy in keeping with the European Society of Medical Oncolgogy ESMO)-European-Society of Gynaecological Oncology (ESGO) consensus recommendations [22]. Increasing age was associated with reducing rates of receiving standard of care therapy with 35.1% of those over the age of 80 receiving both chemotherapy and surgery compared to 78% in those aged 65–69 years (p = 0.000). Ten percent of patients over the age of 80 received no cancer treatment (Figure 1). Six (2%) patients declined surgery and three (1%) declined chemotherapy. Increasing age was associated with lower rates of undergoing cytoreductive surgery (p = 0.001) as well as complete cytoreduction (defined according to the post-operative report) (p = 0.006) with complete cytoreduction obtained in only 28% of those over the age of 80 compared to 69% in those aged 65–69. When optimal cytoreduction (<1 cm residual disease) is reported as a proportion of those patients who underwent surgery, the rates of optimal cytoreduction was 76% in all age cohorts apart from those over 80 where it was 49%. 53.7% of women received standard carboplatin and paclitaxel chemotherapy as first-line treatment. Older women were less likely to receive doublet chemotherapy (19.3% in those over the age of 80 compared to 73.6% in those aged 65–69 years, p = 0.000). Overall, 7.8% women aged 65 and above any form of targeted therapy during first-line treatment. This proportion decreased with advancing age (2.3% of women over the age of 80 compared to 12.4% women between the ages of 65–69 received some form of targeted therapy during first-line treatment (p = 0.05).
Subsequently, the primary treatment of only those women with advanced (Federation of Gynaecology and Obstetrics (FIGO) stage III/IV) disease was assessed. A total of 62.9% of women aged 65 and over received standard of care, with this proportion decreasing significantly with increasing age (p = 0.000). 46.3% of women aged 80 years and over underwent cytoreductive surgery. In these women complete cytoreduction was achieved in 31.6%, compared to those aged between 65–69 years of whom 82.4% underwent surgery, and 69.6% had complete cytoreduction (p = 0.014).
2.3. Treatment Tolerance
Overall, 27.3% of patients developed a grade two or higher haematological toxicity. Neutropenia was more common in younger patients (69.6% in those aged 65–69 vs. 18.8% in those aged 75–79, p = 0.007). Older patients did not experience higher rates of severe haematological toxicity (p = 0.554). However, increasing age was associated with a trend towards a higher rate of G3 or 4 non-haematological toxicities although this did not reach statistical significance (32.5% vs. 13.4% in those aged >80 years vs. those aged 65–69 years, p = 0.082). Increasing age was significantly associated with a lower likelihood of completing 6 cycles (p = 0.034). Of the 38 (15.8%) women who discontinued treatment early, 21 (55%) did so because of toxicity. Discontinuation due to toxicity was higher in older patients, for example 54.5% of 75–79-year-olds compared to 36.4% of those aged 65–69 years, although this did not reach statistical significance (p = 0.15). 28.5% of all patients were admitted to hospital as an emergency at some stage during their primary treatment with no variation due to age (p = 0.135), 30-day mortality was 1.24% across the whole cohort and did not vary according to age (p = 0.184) (Table 3).
2.4. Treatment at Relapse
At first relapse, 50.4% of women received chemotherapy; however, older women were significantly less likely to receive second-line chemotherapy at progression. A total of 35.5% of women over the age of 75 received chemotherapy at relapse, compared to 62.5% of those aged 65–69 years (p = 0.021). One patient (aged 75 years) underwent secondary debulking surgery. Seventy-five women (59% of those who had treatment for relapsed disease) received carboplatin-based chemotherapy at first relapse. Of those who received chemotherapy at first relapse, 56 (45%) received a carboplatin doublet regimen (paclitaxel, pegylated liposomal doxorubicin or gemcitabine with or without a targeted agent for example, bevacizumab). Nineteen (15%) women received single-agent carboplatin. Of those who received platinum at first relapse, 65% achieved some degree of tumour shrinkage as their best response according to the local radiological report with 89% achieving at least stable disease. In those patients who received non-platinum containing regimens, 21 patients (15%) received weekly paclitaxel resulting in a 33.3% radiological response rate and a 52% clinical benefit rate (defined as patients who achieved at least stable disease as their best response documented). Twenty-three (18.9%) patients received either pegylated liposomal doxorubicin or doxorubicin. No responses were seen in this group although 6 (26%) patients had stabilisation of their disease.
2.5. Survival Outcomes
Median overall survival (OS) for all patients was 31.5 months. For patients diagnosed with stage III and stage IV disease, median OS was 28.3 and 14 months respectively. 1-year and 5-year survival was 78.1% (95% CI 72.7–82.5) and 28.7% (95% CI 22.5–35.2) respectively. Overall survival was broadly equivalent over the first three age cohorts however patients over the age of 80 had a significantly lower survival than those aged 65–69 years (median OS 20.02 months vs. 44.91 months, p = 0.000) (Figure 2). First line carboplatin/paclitaxel combination chemotherapy was associated with improved survival outcomes compared to single-agent carboplatin (OS 39.5 vs. 30.6 months), those patients who received no chemotherapy had an OS of 9.7 months (p = 0.003). Progression-free survival (PFS) was similar across all age groups up to the age of 80 but patients aged 80 years and over had a median PFS of 12.3 months compared to 16.4 in those aged 65–69 years (HR 2.0 p = 0.00) (Figure 2).
In univariate analysis, age over 80 years at diagnosis, FIGO stage III/IV disease, incomplete cytoreduction and an ECOG PS of greater than 1 were all associated with poorer survival outcomes. Of the baseline factors and comorbidities collected, the presence of cardiovascular disease (p = 0.043), polypharmacy (p = 0.011) or having a current or past history of smoking (p = 0.008) were all associated with poorer survival outcomes. Requiring assistance with activities of daily living (ADL) (p = 0.000), reporting reduced ADLS (p = 0.000) and weight loss at diagnosis (p = 0.015) were associated with poorer survival outcomes (Table 4). Of the biochemical parameters collected, having any degree of hypoalbuminaemia (p = 0.000) or baseline haemoglobin of less than 110 g/L (p = 0.000) were associated with poorer survival outcomes. GFR was associated with poorer survival as a continuous variable (p = 0.036) however using a threshold of a GFR of 60 mL/min (CKD 3) was not associated with poorer survival outcomes (p = 0.064) (Table 4).
A cox proportional hazards multivariate model was built including treatment-related factors that were predictive, by univariate analysis for overall survival. When adjusted for FIGO stage, surgical outcome, chemotherapy treatment and completion of chemotherapy, age over 80-years-old was no longer an independent risk factor for poorer overall survival. Completion of chemotherapy remained independently associated with overall survival where single-agent versus platinum-doublet chemotherapy was not associated with a significantly different in overall survival in either univariate or multivariate analysis (Table 5).
3. Discussion
This study provides a useful insight into the current real-world treatment of older women diagnosed with epithelial ovarian cancer in two UK cancer centres. There were very low rates of unclassifiable tumours in this series compared to national cancer registry data where over 50% of women over the age of 80 had an unclassified epithelial or miscellaneous tumour [3]. The lack of relationship between unclassifiable tumours and increasing age suggests either an improvement in the approach to the diagnostic process in older patients with more women having a true histological diagnosis being pursued, or the importance of cancer centre management of presumed ovarian cancer. Delayed time to diagnosis and therefore later stage at diagnosis has also been postulated as a cause for poorer survival rates however, stage distribution also did not vary with age in this population with the majority of women of all ages being diagnosed with stage 3 and 4 disease.
In this series, older patients were more likely to have a poorer ECOG performance status however it is well recognised that ECOG performance status alone is a crude measure in an elderly population that does not accurately reflect the functional and comorbid status of older patients [23,24] and it has also been previously shown that poor performance status should not necessarily preclude first-line treatment in epithelial ovarian cancer due to the high response rates observed to platinum-based chemotherapy [25]. Although many older women maintain fit and active lives, a quarter of the study population reported reduced activities of daily living in the preceding weeks and months before their diagnosis. A significant proportion of women in this study also reported living alone, whilst not a concern in and of itself, living alone without sufficient social network or community support particularly in the context of frailty is a challenge for both patients and oncologists when systemic anti-cancer therapy is being considered.
The most striking difference between the oldest patients and those younger than 80 years was that seen in primary treatment received. Under-treatment has long been postulated as one of the primary reasons for the poorer outcomes in older patients. A large retrospective study in France assessed the impact of age on treatment and survival outcomes whether or not guideline-recommendations for therapy were followed between 1997 and 2011. Women 70 years and over compared to those younger were less likely to undergo surgery (60.9% versus 89.6%, p < 0.0001) or receive chemotherapy (57.4% versus 76.4%, p < 0.0001). Only 31.9% of patients 70 years and over underwent both surgery and chemotherapy [26]. A prospective study (OVCAD) that included 275 women treated for primary ovarian cancer between 2005 and 2008 also showed that older women were less likely to receive optimal therapy and had poorer progression-free and overall survival. In multivariate analysis, age was an independent risk factor for poorer overall but not progression-free survival [27]. Our findings confirm that older women continue to receive less treatment than their younger and middle-aged counterparts and this is likely to be a significant factor in explaining the poorer outcomes seen in this population. A limitation of this work is that it was not possible from this retrospective study to ascertain whether, in those patients who did not receive either surgery or chemotherapy whether this decision was patient or clinician-led. Documentation of the rationale for a decision for not treatment should be consistently recorded in patient records. In addition, interview studies of the multidisciplinary team making treatment decisions may shed more light on the rationale for patients not receiving standard of care. It has previously been shown that older women desire cure as much as their younger counterparts and are more willing to undergo potentially disfiguring surgery to achieve this than younger patients [28]. In work also undertaken by our group (manuscript under review), we report that older patients desired active treatment and did not consider their age to be a hindrance.
The difference in survival for the oldest patients becoming no longer statistically significant once FIGO stage, surgical outcome and crucially, chemotherapy received are incorporated into the model provides further evidence that if even the oldest patients receive optimal therapy, survival outcomes are comparable. It has been shown that medical and social optimisation of older patients prior to and during systemic anti-cancer therapy can improve chemotherapy completion rates [29]. This approach is being tested in a wider scale in both the PREPARE [30] and GIVE (NCT02785887) studies; these potentially practice-changing results are awaited. We report here that older patients were less likely to receive targeted therapy, however, the only targeted therapy available during the study period was bevacizumab, which only received NICE approval in 2013 (i.e., the final two years of the study period) and thus these rates may not be fully representative.
Haematological toxicity rates were comparable across the age groups however increasing age was associated with a trend towards a higher rate of non-haematological toxicities. Increasing age was associated with higher early treatment discontinuation rates. This is in keeping with post-hoc analysis from the first-line phase 3 AGO-OVAR3 study, which also showed that women 70 years and over experienced comparable rates of toxicity but were more likely to discontinue treatment early [31]. The AGO-OVAR authors in 2007 suggested a potential difference in attitude towards the treatment of older adults. It can be postulated that this difference persists today. It was relatively rare for patients in our study to decline treatment with six patients declining surgery and three declining chemotherapy; however, the more nuanced decision-making over reducing treatment intensity and early treatment cessation is difficult to reliably elucidate retrospectively. A recent study from the Netherlands reported no treatment rates of 16%; in 40% of these cases it was patient choice, and in 29% it was poor condition in the opinion of the physician [32]. The perspectives of older women on treatment intensity, tolerance and treatment goals are worthy of further study, as the reasons for the reduced treatment intensity remain unclear.
4. Materials and Methods
Local study approvals were received from the Royal Marsden NHS Foundation Trust and The Royal United Hospitals Bath NHS Foundation Trust (SE486). This was a retrospective observational evaluation of all women over the aged 65 and over treated consecutively for newly diagnosed epithelial ovarian cancer (including tubal and primary peritoneal) over a 5-year period (December 2009 to August 2015) in two UK NHS Cancer Centres. Standard of care treatment was defined as undergoing cytoreductive surgery at any stage in the primary treatment pathway in combination with platinum-based chemotherapy. Details of treatment received, medical comorbidities, polypharmacy, functional level at baseline (where possible) as well as routinely assessed haematological and biochemical parameters were collected. Where toxicities had not been graded in real-time, according to the description of the event, retrospective grading was applied using CTCAE v4.0 for all grade haematological and grade ≥3 non-haematological toxicities.
The primary objective was to assess the proportion of women over the age of 65 who are offered and receive standard of care first-line management. Secondary objectives included assessment of progression-free and overall survival from first diagnosis and first relapse; proportion of patients who suffered a severe haematological or non-haematological chemotherapy toxicity; proportion of patients who received treatment for relapsed disease; rate of hospitalisation and 30-day mortality during chemotherapy. Patients were considered eligible if they were aged 65 years or older at the time of a first new patient appointment with a histologically or cytologically confirmed diagnosis of epithelial ovarian, primary peritoneal and fallopian tube carcinoma at either institution.
Statistical Considerations
Chi squared test was used to compare patient baseline characteristics and treatment patterns according to age. Progression-free survival was measured from start of treatment to date of progression or death from any cause. Overall survival was defined as the time from date of diagnosis or date of relapse (depending on the endpoint) to death. Patients without an event were censored at last follow up. Data were censored on the 1 August 2016. Survival outcomes were estimated using the Kaplan–Meier method. Hazard ratios for survival, adjusted for factors likely to be of significance such as age, stage and treatment received were calculated using a cox proportional hazards model. All tests are two sided. A p-value of < 0.05 was used to determine statistical significance. All statistical analyses were performed using Stata IC v15.
5. Conclusions
The oldest women continue to receive lower rates of optimal first-line therapy compared to younger women. Once adjusted for FIGO stage, surgical outcome and first-line treatment received, age was no longer an independent risk factor for poorer overall survival. Not receiving standard of care platinum-based chemotherapy and cytoreductive surgery would therefore appear to be a critical factor for the poorer survival outcomes seen in our oldest patients. In the absence of a formal geriatric or frailty assessment, using age alone may lead to inappropriate under-treatment, adversely affecting cancer outcomes in these women. Further assessment of the reasons behind the lower treatment rates in the oldest patients are essential to further understand and were beyond the scope of this retrospective study. Previous work by this group (manuscript under review) has demonstrated that older women desire active treatment and do not consider their age to be a hindrance. A formal frailty or geriatric assessment together with interventions to address issues identified would assist in optimising vulnerable patients. This could improve the rates of treatment delivery and completion in older adults thereby improving outcomes in this key demographic. The prospective UK FAIR-O study (NCT04300699) seeks to address the issue of assessment and management of frailty and medical comorbidities in the general oncology clinic.
Acknowledgments
We acknowledge the contribution of the late Professor Martin Gore CBE who supervised and supported this study.
Author Contributions
Conceptualization: L.D. and S.B.; methodology, L.D., R.B. and S.B.; investigation L.D. and R.B.; data curation, L.D., R.B., J.B. and S.B.; original draft preparation, L.D.; study idea, data acquisition, statistical analysis, preparation of the first draft of the manuscript, writing—review and editing, L.D., R.B., J.B. and S.B. All authors have read and agreed to the published version of the manuscript.
Funding
Lucy Dumas was part-supported by the London Cancer Alliance-Biomedical Research Centre and the Lady Garden Foundation.
Institutional Review Board Statement
Local study approvals were received from the Royal Marsden NHS Foundation Trust and The Royal United Hospitals Bath NHS Foundation Trust (SE486).
Informed Consent Statement
This study was approved as a service evaluation (exempt from patient-level consent) by the Royal Marsden Hospital Committee for Clinical Research.
Data Availability Statement
The data presented here are available on request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 First-line treatment received according to age cohort.
Figure 2 (A) Overall survival according to age cohort. (B) Progression-free survival according to age cohort.
cancers-13-00952-t001_Table 1 Table 1 Patient characteristics: stage and ECOG performance status at baseline.
65–69 Years n = 91 70–74 Years n = 79 75–79 Years n = 53 >80 Years n = 57 Total n = 280 p
n (%) n (%) n (%) n (%) n (%)
FIGO Stage
1 13 (14.3) 4 (5.1) 8 (15.1) 12 (21.1) 37 (13.2) 0.293
2 9 (9.9) 10 (12.7) 3 (5.7) 3 (5.3) 28 (10.0)
3 52 (57.1) 44 (55.7) 33 (62.3) 29 (50.9) 158 (56.4)
4 16 (17.6) 21 (26.6) 6 (11.3) 12 (21.1) 55 (19.6)
Unknown 1 (1.1) 0 0 1 (1.8) 2 (0.7)
ECOG PS
0 30 (33.0) 12 (15.2) 9 (17.0) 5 (8.8) 56 (20.0) 0.008
1 34 (37.4) 38 (48.1) 27 (50.9) 23 (40.4) 122 (43.6)
2 14 (15.4) 18 (22.8) 8 (15.1) 15 (26.3) 55 (19.6)
3 5 (5.5) 9 (11.4) 3 (5.7) 9 (15.8) 26 (9.3)
Unknown 8 (8.8) 2 (2.5) 6 (11.3) 5 (8.8) 21 (7.5)
Histological subtype
High grade serous 62 (68.1) 57 (72.2) 36 (67.9) 40 (70.2) 195 (69.6) 0.547
Low grade serous 3 (3.3) 3 (3.8) 3 (5.7) 3 (5.3) 12 (4.3)
Carcinosarcoma 6 (6.6) 5 (6.3) 4 (7.5) 6 (10.5) 21 (7.5)
Clear cell 8 (8.8) 1 (1.3) 2 (3.8) 1 (1.8) 12 (4.3)
Endometrioid 7 (7.7) 3 (3.8) 2 (3.8) 2 (3.5) 14 (5.0)
Mucinous 1 (1.1) 2 (2.5) 0 0 3 (1.1)
Adenocarcinoma/Mixed/ Undifferentiated 4 (4.4) 8 (10.1) 6 (11.3) 5 (8.8) 23 (8.2)
cancers-13-00952-t002_Table 2 Table 2 Patient characteristics. Medical comorbidities and functional status at baseline.
65–69 Years n = 91 70–74 Years n = 79 75–79 Years n = 53 >80 Years n = 57 Total n = 280 p
n (%) n (%) n (%) n (%) n (%)
Medical comorbidities
Cardiovascular disease 26 (28.6) 21 (26.6) 16 (30.2) 14 (24.6) 77 (27.5) 0.907
Hypertension 37 (40.7) 28 (35.4) 22 (41.5) 26 (45.6) 113 (40.4) 0.650
Previous malignancy 5 (5.5) 4 (5.1) 6 (11.3) 1 (1.8) 16 (5.7) 0.183
Endocrine disease 7 (7.7) 5 (6.3) 5 (9.4) 3 (5.3) 20 (7.1) 0.834
Osteoarthritis 4 (4.4) 5 (6.3) 7 (13.2) 4 (7.0) 20 (7.1) 0.252
Rheumatological disease 2 (2.2) 7 (8.9) 2 (3.8) 1 (1.8) 12 (4.3) 0.122
CVA/MI/CAD 7 (7.7) 4 (5.1) 6 (11.3) 3 (5.3) 20 (7.1) 0.512
Haematological disease 0 2 (2.5) 0 0 2 (0.7) 0.167
Previous DVT 15 (16.5) 8 (10.1) 8 (15.1) 4 (7.0) 35 (12.5) 0.345
Polypharmacy (>3 meds) 31 (34.1) 27 (34.2) 23 (43.4) 30 (52.6) 111 (39.6) 0.010
Respiratory disease 6 (6.6) 15 (19.0) 6 (11.3) 1 (1.8) 28 (10.0) 0.007
Diabetes 9 (9.9) 7 (8.9) 6 (11.3) 7 (12.3) 29 (10.4) 0.850
Cognitive impairment 0 2 (2.5) 0 6 (10.5) 8 (2.9) 0.001
Depression 6 (6.6) 4 (5.1) 0 1 (1.8) 11 (3.9) 0.193
Functional baseline
Lives alone 20 (22.0) 31 (39.2) 18 (34.0) 29 (50.9) 98 (35.0) 0.000
Lives in supported accommodation 0 1 (1.3) 2 (3.8) 4 (7.0) 7 (2.5) 0.032
Use of walking aids 7 (7.7) 12 (15.2) 11 (20.8) 14 (24.6) 44 (15.7) 0.026
Reduced activities of daily living 16 (17.6) 22 (27.9) 13 (24.5) 19 (33.3) 70 (25.0) 0.226
Assistance with activities of daily living 7 (7.7) 10 (12.7) 8 (15.1) 10 (17.5) 35 (12.5) 0.441
History of delirium in last 12 months 0 0 0 3 (5.3) 3 (1.1) 0.007
Cognitive impairment 0 2 (2.5) 0 6 (10.5) 8 (2.9) 0.001
Weight loss in last 3 months 22 (24.2) 22 (27.9) 11 (20.8) 11 (19.3) 66 (23.6) 0.799
Visual impairment 3 (3.3) 1 (1.3) 2 (3.8) 9 (15.8) 15 (5.4) 0.016
Hearing impairment 1 (1.1) 0 2 (3.8) 3 (5.3) 6 (2.1) 0.242
History of falls in last 12 months 1 (1.1) 0 1 (1.9) 3 (5.3) 5 (1.8) 0.106
cancers-13-00952-t003_Table 3 Table 3 Treatment tolerance.
65–69 Years
n = 82 70–74 Years
n = 72 75–70 Years
n = 48 >80 Years
n = 39 Total
n = 241 p-Value
% % % % %
Dose modification at baseline 9.8 12.5 6.3 17.5 11.6 0.365
Dose modification during chemotherapy 29.3 30.6 52.1 37.5 35.5 0.193
Completed 6 cycles of chemotherapy 86.6 86.1 77.1 65.0 82.2 0.034
≥ G2 Haematological toxicity 29.3 19.4 33.3 30.0 27.3 0.554
≥ G3 Non-haematological toxicity 13.4 19.4 27.1 32.5 21.1 0.082
Febrile neutropenia 4.9 2.8 2.1 0.00 2.9 0.540
Hospital admission during chemotherapy 20.7 34.7 25.0 37.5 28.5 0.135
Death within 30 days of chemotherapy 1.2 0.00 4.2 0.00 1.2 0.184
cancers-13-00952-t004_Table 4 Table 4 Univariate and multivariate analysis of factors associated with poorer overall survival.
Univariate Multivariate
n HR 95% CI p HR 95% CI p
Age Cohort 65–69 91 - - - - - -
70–74 79 1.40 (0.96–2.05) 0.081 0.95 (0.60–1.52) 0.833
75–79 53 1.07 (0.68–1.68) 0.772 0.79 (0.44–1.43) 0.441
>80 57 2.20 (1.47–3.27) 0.000 1.76 (1.03–3.02) 0.04
FIGO Stage 1 37 - - -
2 28 1.30 (0.55–3.07) 0.553 7.91 (0.98–63.61) 0.052
3 158 3.69 (1.98–6.89) 0.000 12.99 (1.77–95.20) 0.012
4 55 6.00 (3.08–11.68) 0.000 16.16 (2.11–123.61) 0.007
ECOG PS 0 56 - - -
1 122 1.86 (1.18–2.93) 0.007 2.14 (1.21–3.79) 0.009
2 55 4.02 (2.47–6.53) 0.000 2.53 (1.20–5.35) 0.015
3 26 7.36 (4.13–13.13) 0.000 3.51 (1.37–8.99) 0.009
Cardiovascular disease 77 1.38 (1.01–1.90) 0.043 0.99 (0.62–1.57) 0.95
Taking 3 or more medications 111 0.07 (0.01–0.55) 0.011 1.12 (0.72–1.74) 0.62
Osteoarthritis 16 1.70 (0.96–3.01) 0.070 1.62 (0.76–3.44) 0.209
Reduced activities of daily living 70 2.89 (2.10–3.98) 0.000 1.53 (0.90–2.62) 0.118
History of depression 11 1.86 (0.95–3.65) 0.071 1.89 (0.83–4.30) 0.128
History of weight loss 66 1.51 (1.09–2.11) 0.015 0.93 (0.59–1.47) 0.754
Albumin <35 g/L 114 2.09 (1.56–2.81) 0.000 1.52 (0.97–2.38) 0.065
Haemoglobin <120 g/L 141 1.28 (0.9601.72) 0.093 0.80 (0.53–1.23) 0.311
GFR <60 mL/min 104 1.33 (0.98–1.79) 0.064 1.11 (0.74–1.68) 0.607
cancers-13-00952-t005_Table 5 Table 5 Univariate and multivariate factors associated with poorer overall survival.
Univariate Multivariate
HR 95% CI p HR 95% CI p
Age Cohort 65–69 years - - - - - -
70–74 years 1.40 (0.96–2.05) 0.081 1.22 (0.77–1.95) 0.386
75–79 years 1.07 (0.68–1.68) 0.772 0.85 (0.46–1.54) 0.582
>80 years 2.20 (1.47–3.27) 0.000 0.81 (0.40–1.61) 0.541
FIGO stage 1 - - -
2 1.30 (0.55–3.07) 0.553 2.39 (0.86–6.64) 0.094
3 3.69 (1.98–6.89) 0.000 4.38 (2.02–9.52) 0.000
4 6.00 (3.08–11.68) 0.000 6.96 (2.81–17.24) 0.000
Surgical outcome Residual disease 2.71 (1.82–4.03) 0.000 2.09 (1.32–3.30) 0.002
Platinum- combination - - - - - -
Chemotherapy Single-agent carboplatin 1.29 (0.93–1.77) 0.123 1.34 (0.85–2.17) 0.203
No chemotherapy 2.19 (1.43–3.35) 0.000 4.49 (1.99–10.13) 0.000
Completed 6 cycles 0.34 (0.23–0.49) 0.000 0.33 (0.19–0.59) 0.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BEVACIZUMAB, CARBOPLATIN, DOXORUBICIN, GEMCITABINE, PACLITAXEL | DrugsGivenReaction | CC BY | 33668809 | 19,724,626 | 2021-02-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pathogen resistance'. | Genetic and Phenotypic Characterization of in-Host Developed Azole-Resistant Aspergillus flavus Isolates.
Aspergillus flavus is a pathogenic fungal species that can cause pulmonary aspergillosis, and triazole compounds are used for the treatment of these infections. Prolonged exposure to azoles may select for compensatory mutations in the A. flavus genome, resulting in azole resistance. Here, we characterize a series of 11 isogenic A. flavus strains isolated from a patient with pulmonary aspergillosis. Over a period of three months, the initially azole-susceptible strain developed itraconazole and voriconazole resistance. Short tandem repeat analysis and whole-genome sequencing revealed the high genetic relatedness of all isolates, indicating an infection with one single isolate. In contrast, the isolates were macroscopically highly diverse, suggesting an adaptation to the environment due to (epi)genetic changes. The whole-genome sequencing of susceptible and azole-resistant strains showed a number of mutations that might be associated with azole resistance. The majority of resistant strains contain a Y119F mutation in the Cyp51A gene, which corresponds to the Y121F mutation found in A. fumigatus. One azole-resistant strain demonstrated a divergent set of mutations, including a V99A mutation in a major facilitator superfamily (MSF) multidrug transporter (AFLA 083950).
1. Introduction
Chronic pulmonary aspergillosis (CPA) is a relatively uncommon pulmonary disease, occurring in apparently nonimmunocompromised patients. The disease often affects patients with other respiratory disorders such as chronic obstructive pulmonary disease, tuberculosis, nontuberculous mycobacteria (NTM) infection, prior pneumothorax or treated lung cancers [1,2]. Aspergillus fumigatus is the causative species of CPA in the majority of patients, but other species such as A. niger, A. terreus and A. flavus may also be cultured from patients with CPA [3]. Subacute invasive aspergillosis (SAIA) is another clinical presentation of pulmonary aspergillosis occurring in mild immunocompromised patients. The clinical and radiological features are very similar to CPA, but the progression of the disease is more rapid. In contrast to CPA, serum galactomannan is often positive in SAIA. However, SAIA has a slower course of progression (one to three months) compared to acute invasive aspergillosis [1]. Symptomatic or progressive CPA is treated primarily with itraconazole, but voriconazole and posaconazole are potential alternative agents [1,4]. Patients with SAIA should always be treated with antifungals according to the CPA guideline. Voriconazole and isavuconazole are regarded as first-line agents for these patients [1,4].
Azole resistance in A. fumigatus is reported in many countries worldwide and challenges the treatment of Aspergillus diseases [5,6]. Although azole resistance has also been described in A. flavus isolates, the mechanism of azole resistance has been less extensively studied in A. flavus compared to A. fumigatus. Azole-resistant infections may be due to the direct inhalation of resistant spores present in the environment. Alternatively, azole resistance may develop during azole treatment, characterized by a phenotype switch from drug susceptible to drug resistant [7,8]. The latter occurs primarily in patients with chronic forms of aspergillosis receiving long-term therapy and especially in those with pulmonary cavities [9,10].
Here, we describe a patient who was treated for SAIA. During antifungal treatment, several A. flavus isolates were cultured. The sequentially cultured isogenic isolates in this study showed a highly variable macroscopic morphology. The first two isolates appeared to be azole susceptible, and the following nine isolates had increased MICs for voriconazole and itraconazole. Azole resistance generally comes with a fitness cost, which may become apparent through growth variation when resistant isolates are cultured in the absence of azole pressure under laboratory conditions [11]. In A. fumigatus, similar variations in colony morphology were observed in sequential cultures [12]. To further understand in-host adaptation dynamics of A. flavus during antifungal treatment, we performed genetic analysis of 11 cultured A. flavus isolates from consecutive cultures obtained from a single patient during azole treatment for SAIA.
2. Materials and Methods
2.1. Origin of Strains and Antifungal Treatment
The 11 strains used in this study were cultured from a 66-year-old female with COPD Gold IIA. One and a half years prior to the first A. flavus culture, computed tomography (CT) of the lungs showed a cavity, and subsequent biopsy culture showed Mycobacterium intracellulare, which was treated with clarithromycin. Eight months later, CT showed an aspergilloma in the pre-existing cavity, and the patient was treated with voriconazole for six weeks. As the patient’s condition worsened, with progressive weight loss and recurrent hemoptysis, she was referred to the University Medical Centre (Nijmegen, the Netherlands) for the optimization of nontuberculosis mycobacterial treatment. Her antimycobacterial therapy was changed to clarithromycin, rifampicin and ethambutol. No clinical improvement was observed, and two sputum cultures showed A. flavus (Isolates 1 and 2), which prompted a diagnostic work-up for CPA (Figure 1 and Figure 2). The serum galactomannan (GM) index (2.0), Aspergillus IgG (43 mg/L) (ImmunoCap) and IgE antibodies (0.44 kU/L) were positive, which, together with her CT scan abnormalities, were consistent with SAIA. Antifungal treatment was again started with liposomal amphotericin B (L-AmB). Although A. flavus may be less susceptible to L-AmB treatment, the concurrent use of rifampicin precluded azole therapy, and L-AmB was chosen as the second-best option. After six weeks, both L-AmB and rifampicin were stopped due to side effects. The serum GM index had declined to 0.6. The patient was subsequently treated with voriconazole, which was changed to itraconazole after two weeks due to visual disturbances. During this therapy, A. flavus was cultured from sputum, which now showed an azole-resistant phenotype (Isolate 3), and antifungal treatment was changed to anidulafungin. In addition, terbinafine was started as the terbinafine MICs were low, and the combination was aimed to prevent or delay further resistance selection. As symptoms worsened and serum GM increased to 3, L-AmB was restarted after five weeks. As no improvement was observed despite continued antifungal and tuberculostatic agents, antifungal treatment was stopped, and the patient was discharged. The patient remained stable for some time after discharge but eventually died after 12 months.
Over a six-month period, 11 isolates were cultured from the patient, and all were morphologically identified as A. flavus at the Centre of Expertise in Mycology Radboudumc/CWZ. Isolates were stored at −80 ℃ in 10% glycerol. In vitro susceptibility testing of the isolates was performed according to the EUCAST broth microdilution reference method for molds (E.def 9.2) [13]. Isolates were tested at a final drug concentration range of 0.032–16 mg/L for itraconazole, voriconazole and posaconazole. The endpoint defined as no growth was visually determined. Susceptibility testing was performed at the time the isolates were cultured, and the results were confirmed by reviving the isolates and repeating the susceptibility testing. Short tandem repeat (STR) typing was performed as described previously using three sets of three markers (AflaSTR2, AflaSTR3 and AflaSTR4) [14,15]. The isolates were phenotyped by studying the colony morphology on agar media (creatine agar (CREA), Czapek yeast extract agar (CYA) incubated at 25, 37 and 40 °C, CYA supplemented with 5% NaCl (CYAS), dichloran 18% glycerol agar (DG18), malt extract agar (MEA), Sabouraud dextrose agar (SAB) and yeast extract sucrose (YES) agar). The agar media were inoculated in a three-point position and incubated for 7 days at 25 °C (unless stated otherwise) in darkness. The composition of the media is according to Samson et al. [16]. Partial β-tubulin (BenA), calmodulin (CaM) and RNA polymerase II second largest subunit (RPB2) sequencing were performed as previously described [17].
2.2. Whole-Genome Sequencing and Analysis
Genomic DNA was extracted from conidia. Conidia were suspended in Tris–EDTA buffer (pH 8, supplemented with 1% SDS, 2% Triton × 100 and 100 mM NaCl). The suspension was shaken for 30 min at 70 °C. DNA was extracted using phenol/chloroform and purified using the QIAamp DNA Blood Mini kit (Qiagen, Aarhus, Denmark). A fragmented genomic DNA library was prepared using a Nextera XT DNA sample preparation kit (Illumina, San Diego, USA). Subsequent sequencing was conducted in a paired-end 2 × 150 bp mode using an Illumina NextSeq500 machine. Reads were mapped to the Aspergillus flavus NRRL3357 (Assembly GCA_000006275.2, EnsemblFungi) and Aspergillus oryzae RIB40 (ASM18445v3) (Assembly GCA_000184455.3, EnsemblFungi) reference genomes using CLC Genomics Workbench 12 (Qiagen, Aarhus, Denmark). Single-nucleotide polymorphism (SNP) detection and variant comparisons were conducted using CLC Genomics Workbench 12 (Qiagen) and the Basic Variant Detection method with ploidy 1, a minimum coverage of 5 and a minimum probability of 0.8.
Whole-genome sequencing data from 14 A, flavus and A. oryzae strains were obtained from the NCBI SRA database (Appendix A Table A1). Contigs were generated by de novo assembly using sequencing reads from all clinical samples and reference strains. Whole-genome alignment was performed on sets of contigs with a minimum size of 10 kb. Whole-genome alignment and pairwise comparison were performed using the Whole-Genome Alignment tool implemented in CLC Genomic Workbench version 20.0.4 with default settings [18]. The generated distance matrix, based on the average nucleotide identity (ANI), was used to calculate the neighbor-joining phylogenetic relationships (Figure 3).
SNP-calling on the various clinical samples was done by mapping reads of individual strains to contigs obtained from strain V159-40 as a reference genome. Variants were determined by the Basic Variant Detection tool in CLC Genomics Workbench version 20. The ploidy number was set to one and the minimum frequency filter to 95%. Default values were used for all other parameters and variant filters. Sequences containing SNPs present in a total of 177 positions were aligned using MAFFT [19]. A maximum-likelihood phylogenetic tree was calculated using CLC Genomics Workbench version 20.
3. Results
3.1. Strains, Phenotypical Analysis and Genotyping
Partial BenA, CaM and RPB2 sequencing confirmed the morphological species identification as A. flavus. All isolates had identical BenA, CaM and RPB2 sequences. The results of the susceptibility testing are shown in Table 1. Isolates 1 and 2 had low MICs for the azoles, and the azole MICs of Isolates 3–11 were increased compared to Isolates 1 and 2. Repeated testing of isolates showed similar MICs (within two dilution steps) for all isolates, except Isolate 4. For Isolate 4, the increased MICs could not be reproduced, even after subculturing the isolate on azole-containing agar first. The MIC of amphotericin B was either 1 or 2 mg/L for all isolates, and the MIC of anidulafungin ranged from 0.016 to 0.025 mg/L (Table 1).
Growth analysis of the isolates at eight different conditions revealed a diverse colony morphology (Figure 4 and Figure A1), and none of the isolates were phenotypically identical. Isolates 1 and 2 showed typical spreading A. flavus colonies, with abundant sclerotia production on CYA incubated at 25 °C and yellow-green-colored conidia. Isolate 5 resembled Isolates 1 and 2, though sporulation was absent on most agar media, and growth was reduced on DG18. Isolates 3, 6, 8 and 11 had similar colony diameters, and of those isolates, 6 and 11 had a similar degree of sporulation. Compared to Isolates 1 and 2, these isolates had smaller colony diameters on CYAS and DG18. Isolate 4 was unique in producing greenish-brown-colored conidia, and Isolate 9 had very restricted growth, unlike all other isolates. Isolates 7 and 10 resembled each other in colony diameters, though Isolate 7 sporulated more strongly. Short tandem repeat genotyping revealed full genetic relatedness between all isolates, suggesting that the isolates originate from the same parent strain. The tandem repeat numbers are shown in Table 1.
3.2. Whole-Genome Sequence Analysis
Aspergillus flavus NRRL3357 and A. oryzae RIB40 were used as reference genomes for read mapping based on an assessment of mapping quality and coverage statistics; a mean coverage of approximately 40 and a mean mapping quality score of 40 were found across the sequenced isolates. A total of 31 nonsynonymous SNPs, absent in early Isolates 1 and 2, were identified in later isolates (Table 2). The cyp51A mutation Y119F (corresponding to the Y121F mutation in A. fumigatus) was found in Isolates 3 and 5-11 but not in Isolate 4. Isolates 3, 5, 6, 8, 9 and 11 had a mutation in a gene with putative C-4 methyl sterol oxidase function, resulting in a stop codon at Locus 35. Isolate 4 did have a point mutation in a putative major facilitator superfamily (MFS) transporter (AFLA_083950). Phylogenetic relationship analysis based on whole-genome sequencing data confirmed the results based on short tandem repeat genotyping. All sequential cultured strains showed a genetic relationship (Figure 3). Phylogenetic relationship analyses of the 11 cultured A. flavus strain showed that Isolates 2, 7 and 10 were genetically highly similar to each other. Isolates 3, 6, 8, 9 and 11 were more genetically related to each other (Figure A2).
4. Discussion
Here, we describe the characteristics of 11 A. flavus isolates that were cultured during the treatment of SAIA in a patient with chronic lung disease. All isolates were identified as A. flavus and had identical partial BenA, CaM and RPB2 gene sequences, showing high genetic similarity. STR analysis and whole-genome sequencing further confirmed the isogeneity of all isolates. The isolates were macroscopically very diverse and later isolates showed decreased in vitro susceptibility to azoles.
Azole resistance is an increasing problem worldwide, especially in A. fumigatus. [20]. However, reports on azole resistance in A. flavus are sparse, and the resistance mechanisms are generally unknown. Several single-nucleotide polymorphisms (SNPs) have been reported in the A. flavus Cyp51 genes encoding lanosterol 14 alpha-demethylase. This protein is the target of azoles, and the A. flavus genome contains three orthologs of this gene. One study demonstrated S196F, A324P, N423D and V465M polymorphisms in the Cyp51C gene in an azole-resistant isolate [21]. However, another study identified the same SNPs in both azole-susceptible and azole-resistant isolates, arguing against the association of these mutations for azole resistance [22]. Another study suggested the role of the S240A SNP in the Cyp51C gene. They found an S240A SNP in an isolate with increased voriconazole MICs and confirmed its role in voriconazole tolerance by transformations [23]. However, again, this SNP was also found in many azole-susceptible isolates [21,22,24]. The last SNP in Cyp51C that was suggested to play a role in azole susceptibility is Y319H [24]. In laboratory-selected resistant isolates using voriconazole stress, both Cyp51A and Cyp51B mutations were identified compared to the parental strain. K197N, Y132N+T469S and K197N+D282E+M288L SNPs were found in the Cyp51A of isolates with increased voriconazole MICs, and H399P+D411N and T454P+T486P were observed in the Cyp51B of 2 other isolates [25]. However, a direct relationship with azole resistance was not established. In addition, other non-cyp51-mediated mechanisms, such as azole efflux, due to the overexpression of ATP-binding cassettes (ABC) and MFS transporters, have been suggested to play a role in azole resistance in A. flavus. [26].
We identified a novel Y119F substitution in the cyp51A gene, which seemed to be the cause of the azole resistance phenotype in eight of nine azole-resistant isolates. Although the relation of the Y119F mutations and azole resistance is not formally proven, strong indirect evidence is available. First, the mutation was observed in azole-resistant strains, and the genetically identical parental isolates without this mutation were susceptible. Secondly, in A. fumigatus, the homolog Y121F mutation is directly linked to increased voriconazole MICs, and this phenotype is supported by a CYP51A homology protein model [27,28]. Furthermore, Y119F-corresponding homologous mutations in other fungal species have similar effects on azole susceptibility. For example, the homolog Y132F mutation has been described in azole-resistant Candida albicans and was also found in azole-resistant C. auris and C. parapsilosis isolates [29,30,31]. The homolog Y145F mutation in C. neoformans [32] and the Y136F mutation in the Histoplasma capsulatum cyp51A gene [33] were associated with reduced voriconazole susceptibility. Furthermore, the homolog Y137F mutation in Mycosphaerella graminicola [34] and the Y136F mutation in Uncinula necator [35] are associated with resistance to triadimenol, a triazole that shows structurally more resemblance to voriconazole than to the long-tailed triazole itraconazole and posaconazole. Interestingly, the C. neoformans and H. capsulatum strains with Y145F and Y136F mutations remained susceptible to itraconazole and posaconazole [32,33]. Thus, the increased MICs of voriconazole observed in our isolates are likely explained by the Y119F mutation in the Cyp51A gene. However, itraconazole showed paradoxical growth (eagle effect) in our clinical isolates, where significant growth inhibition was seen at relatively low concentration but only minimal growth inhibition at higher concentrations of itraconazole. Whether the Y119F substitution is causing this phenomenon and whether itraconazole remains clinical effective is not clarified.
Another mutation resulting in a stop codon at Locus 35 found in six of nine azole-resistant isolates might also be involved in adaptation to azole stress. Orthologs of the AFLA_115530 gene, which has a putative C-4 methyl sterol oxidase function, are involved in sterol biosynthesis. The orthologs ERG25 and ERG25b in A. fumigatus are upregulated during azole stress [36]. Furthermore, in vitro itraconazole selection was pressure-selected for a mutation in the ERG25 gene of A. fumigatus. [37]. Although the precise function and its effect on azole susceptibility are largely unknown, azole stress may have resulted in the selection of this mutation. In addition to azole treatment, the patient was treated with L-AmB and anidulafungin, which may select for mutations in the ERG genes or FKS gene. However, none of the isolates had increased L-AmB MICs and SNPs in the FKS gene were not identified.
Isolate 4 did not harbor the Y119F Cyp51A mutation or the mutation putative C-4 methyl sterol oxidase. Initial testing showed increased MICs for itraconazole and voriconazole, but after reviving the stored isolate, repeated testing could not confirm the initially observed phenotype. It could be that this isolate harbored a nonstable resistance mechanism that was lost during storage and subculturing. However, growing the isolate under azole pressure did not reproduce the increased MICs (data not shown). Alternatively, the stored isolate might not have been a pure culture, and reviving and subculturing may have resulted in the selection of a faster-growing nonresistant isolate. Whole-genome sequencing revealed a mutation in the putative MFS transporter (AFLA_083950) gene of this isolate. In A. fumigatus, azole stress increases the expression of the ortholog AFU1G15490 gene, and thus this gene may be involved in the development of azole tolerance [38]. However, further studies would be required to confirm this observation.
Isolates 3, 5, 6, 8 and 11 share a similar mutation pattern and also have similar growth rates (Table A2). Compared to isolates 1 and 2 (wild-type phenotype), all strains grow slower on DG18 and, with the exception of Isolate 5, slower on CYAS (Figure 4). These two agar media have a lowered water activity due to the presence of glycerol (DG18) and NaCl (CYAS). It can be speculated that the evolution of the isolate in the patient led to reduced stress resistance against lowered water activity, a condition not present in the human lung. In contrast, A. fumigatus isolates obtained from humans with suspected invasive pulmonary aspergillosis and dogs with sino-orbital aspergillosis have a higher growth rate on DG18 compared with environmental strains [39]. Isolate 4 has four mutations (R52G, V99A, A561T, T159I) that are not observed in the other isolates. The production of greenish-brown-colored conidia is a unique macro-morphological feature of this isolate and might be linked to one or a combination of these mutations. The function of two genes with mutations is unknown; the other two are an MSF transporter and a global gene regulator VeA. Isolates 7 and 10 resemble each other and these two strains only have the Y119F mutation. These strains have similar growth rates as Isolates 1 and 2 but lack the production of sclerotia and acid production on CREA.
Phylogenetic analysis of the isolates showed that Isolates 2, 7 and 10 were highly similar, indicating these isolates were from the same subpopulation. Isolate 2 was isolated at the beginning of the infections, whereas Isolate 10 was cultured six months later. However, several less-related A. flavus isolates were cultured between Isolates 2 and 10, which possibly represent different subpopulations in the lungs of the patient. This indicates that the patient was initially infected with a single A. flavus strain, which resulted in several subpopulations. Furthermore, it also indicates that these subpopulations of A. flavus were present in the lungs of the patient at the same time. The first azole-resistant isolates were cultured already after one week of voriconazole treatment. It could be that the resistant isolates acquired the resistance-associated mutations during the earlier six weeks’ voriconazole treatment and thus were already present in the lung of the patient. It could be that these resistant isolates were selected during the second treatment with voriconazole. This would explain how the resistant strains could be isolated after a very short course of voriconazole treatment. The clinical samples did not grow strains from every population in every culture that was taken from this patient. Thus, even when a culture from a patient with aspergillosis is positive, it could be that another isogenic population of Aspergillus is present in the lung with a different susceptibility phenotype if SNPs conferring resistance were selected in this subpopulation. Accordingly, as not all subpopulations will be detected in a single culture, patients with CPA treated with antifungal agents should be cultured repeatedly, especially if a pulmonary cavity is present in the lungs or the patient does not improve clinically.
The sequentially cultured isolates in this study were morphologically very diverse. Interestingly, STR and genomic analysis showed that all isolates were isogenic, indicating that the patient was infected with one single isolate. Only few SNPs were found in later isolates compared to the first two cultured isolates. The variable colony morphology may be due to fitness costs associated with resistance development, nutrient availability or adaptation to other host stressors [9,40]. In vitro studies indicate that azole stress may result in morphological variation. The in vitro selection of azole resistance using posaconazole resulted in apparent morphological changes in A. fumigatus colonies [41]. Similar morphological changes were observed in azole-resistant isolates exposed to itraconazole selection pressure [11]. Morphological variation was also seen in consecutive A. fumigatus isolates cultured from a patient with recurrent invasive aspergillosis extensively treated with several antifungals [12]. It is possible that the observed mutations in our isolates underlie the variable phenotypes, but other underlying (epi)genetic mechanisms may be undiscovered. The precise role of the mutations observed in our study regarding the morphological variation remains unknown and could not be explained by the function of the mutated genes alone. Further transformation studies would be needed to further elaborate on the role of these genes. Our observations show that genetically related isolates can be very different morphologically, and genetic relatedness cannot be excluded based on morphology alone [42].
Author Contributions
Conceptualization, P.E.V. and W.J.G.M.; validation, J.B.B. and J.Z.; formal analysis, J.B.B., J.F.M., J.H. and J.Z.; writing—original draft preparation, J.B.B. and J.H.; writing—review and editing, M.H.R., J.Z., M.S., J.F.M., P.E.V. and W.J.G.M.; supervision, P.E.V. and W.J.G.M. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Informed Consent Statement
Patient consent was waived as the patients was deceased.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article.
Conflicts of Interest
The authors declare no conflict of interest.
Appendix A
Figure A1 Overview of the phenotypic diversity of A. flavus isolates (all reverse, 7 days at 25 °C, unless stated otherwise). Columns, left to right: CYA, CYA incubated 37 °C, CYA incubated 40 °C, CYAS, YES, MEA, CREA, DG18, SAB. Rows, top to bottom: Isolates 1–11.
Figure A2 Maximum-likelihood phylogenetic tree of the 11 A. flavus isolates.
jof-07-00164-t0A1_Table A1 Table A1 Strain information including accession numbers of the strains used for phylogenetic analysis based on whole-genome sequencing data.
Accession Number Organism Strain Origin
1 SRR4142427 A. flavus 3357 wt parent Unknown USA
2 SRR5906257 A. flavus WRRL1519 Almond nut Cal. USA
3 SRR6914138 A. flavus ATCC200026 Peanut USA
4 SRR7615260 A. flavus NRRL21882 Peanut USA
5 SRR8554744 A. flavus from corn (Miss. USA) Corn Miss. USA
6 SRR8556699 A. flavus from corn (Miss. USA) Corn Miss. USA
7 SRR11596600 A. flavus 07-S-2-5-7 Corn Louis. USA
8 SRR11596612 A. flavus 07-S-2-5-4 Corn Louis. USA
9 SRR12001143 A. flavus TX-B-1-1-1 Soil USA
10 SRR12001155 A. flavus PA-B-20-3-1 Soil USA
12 SRR7615261 A. oryzae M2040 Industrial strain South Korea
13 SRR1835311 A. oryzae RIB40 Industrial strain unknown
15 DRR163532 A. oryzae TK-82 replicate 2 Industrial strain unknown
16 DRR163631 A. oryzae TK-82 replicate 1 Industrial strain unknown
17 SAMN14278081 A. flavus V152-39 Clinical sample The Netherlands
18 SAMN14278082 A. flavus V152-49 Clinical sample The Netherlands
19 SAMN14278083 A. flavus V156-58 Clinical sample The Netherlands
20 SAMN14278084 A. flavus V158-11 Clinical sample The Netherlands
21 SAMN14278085 A. flavus V158-20 Clinical sample The Netherlands
22 SAMN14278086 A. flavus V158-70 Clinical sample The Netherlands
23 SAMN14278087 A. flavus V158-75 Clinical sample The Netherlands
24 SAMN14278088 A. flavus V158-76 Clinical sample The Netherlands
25 SAMN14278089 A. flavus V158-77 Clinical sample The Netherlands
26 SAMN14278090 A. flavus V159-40 Clinical sample The Netherlands
27 SAMN14278091 A. flavus V159-56 Clinical sample The Netherlands
jof-07-00164-t0A2_Table A2 Table A2 Overview of the amino acid changes of nine A. flavus isolates and the unique macromorphological characteristics.
Isolate Amino Acid Change Colony Diameter (mm, after 7 d, 25 °C) Unique Macromorphological Characters Compared to Isolates 1–2 a
I997N R52G A221T V99A H25Q P38L A561T Y119F K1757R I570T T159I R669Q E35* P445L CYAS DG18
3 x x x x x x x x x x 36–38 32–34 Colony diameters smaller on DG18 and CYAS, sporulation variable
4 x x x x 50–53 >60 Colony diameters slightly smaller on CYAS; greenish-brown-colored conidia
5 x x x x x x x x 54–58 36–38 Colony diameters smaller on DG18, slightly smaller on CYAS; sporulation generally absent or weak
6 x x x x x x x x x 26–30 32–34 Colony diameters smaller on DG18 and CYAS; sporulation variable
7 x >60 >60 Colony diameters similar as Isolates 1–2; abundant sporulation on all agar media, except creatine agar
8 x x x x x x x x x 36–38 29–32 Colony diameters smaller on DG18 and CYAS; sporulation variable
9 x x x x x x 8–10 16–18 Colony diameters restricted on all agar media; sporulation absent
10 x 54–58 >60 Growth diameters slightly smaller on CYAS, sporulation generally moderate or good
11 x x x x x x x x 35–38 30–33 Colony diameters smaller on DG18 and CYAS; sporulation variable
a Isolates 3–11 are compared to isolates 1 and 2; the latter two isolates present a typical A. flavus phenotype with a high growth rate on most media (CYAS: >60 mm, DG18: >60 mm), production of yellow-green-colored conidia and black sclerotia. Isolates 3–11 do not produce sclerotia or acid on creatine agar.
Figure 1 Chest computed tomography image showing a large pulmonary cavity in the left upper lobe with a mass lying in the cavity.
Figure 2 Timeline of the antifungal treatment and A. flavus culture morphology. VCZ, voriconazole; ICZ, itraconazole; L-AMB, liposomal amphotericin B; TRB, terbinafine; ANI, anidulafungin. The dates that clinical samples were obtained from the patient are indicated in the Figure, and the numbering of the isolates is based on the date the cultures became positive. Isolates 7 and 9 were cultured from the same clinical material but showed different morphologies. Isolate 8 was cultured from a clinical sample obtained 2 days after Isolates 7 and 9. This culture was earlier positive than the cultures of Isolate 9.2.2. Strains, phenotypic analysis, antifungal susceptibility and typing.
Figure 3 Neighbor-joining phylogenetic relationships of sequential isolated A. flavus strains and 14 A. flavus and A. oryzae strains obtained from the NCBI SRA database based on whole-genome sequencing data. The phylogenetic relationship was calculated from a distance matrix based on the average nucleotide identity.
Figure 4 Overview of the phenotypic diversity of A. flavus isolates (all obverse, 7 days at 25 °C, unless stated otherwise). Columns, left to right: Czapek yeast extract agar (CYA), CYA incubated 37 °C, CYA incubated 40 °C, CYA supplemented with 5% NaCl (CYAS), yeast extract sucrose (YES), malt extract agar (MEA), creatine agar (CREA), dichloran 18% glycerol agar (DG18), Sabouraud dextrose agar (SAB). Rows, top to bottom: Isolates 1–11.
jof-07-00164-t001_Table 1 Table 1 Overview susceptibility and short tandem repeat (STR) typing of 11 sequentially cultured A. flavus isolates MIC minimal inhibitory concentration.
Strain Number Isolation Date MIC (mg/L) STR Numbers
ITC VOR POSA AMB ANI c 2 3 4
1 V152-39 8-8-2013 0.5 1 0.5 1 0.063 23-14-17 8-22-12 5-7-2011
2 V152-49 12-8-2013 1 4 0.25 2 0.031 23-14-17 8-22-12 5-7-2011
3 V156-58 22-11-2013 16 a >16 0.5 2 0.031 23-14-17 8-22-12 5-7-2011
4 V158-11 31-12-2013 >16 a,b >16 b 1 2 0.063 23-14-17 8-22-12 5-7-2011
5 V158-20 3-1-2014 16 a 16 0.5 1 0.016 23-14-17 8-22-12 5-7-2011
6 V158-70 17-1-2014 2 >16 0.5 2 0.016 23-14-17 8-22-12 5-7-2011
7 V158-75 21-1-2014 >16 a >16 1 2 0.125 23-14-17 8-22-12 5-7-2011
8 V158-76 23-1-2014 >16 a >16 1 2 0.125 23-14-17 8-22-12 5-7-2011
9 V158-77 21-1-2014 1 16 0.25 2 0.25 23-14-17 8-22-12 5-7-2011
10 V159-40 3-2-2014 >16 a >16 2 2 0.031 23-14-17 8-22-12 5-7-2011
11 V159-56 7-2-2014 1 >16 0.5 2 0.016 24-14-17 8-22-12 5-7-2011
STR, short tandem repeats; ITC, itraconazole; VOR, voriconazole; POSA, posaconazole; AMB, amphotericin B; ANI, anidulafungin. a Isolates showed paradoxical growth (eagle effect). Significant growth inhibition was seen at a relatively low concentration but only minimal growth inhibition at higher concentrations of itraconazole. b The MIC results could not be reproduced. Repeated testing showed a MIC of 0.25 mg/L for itraconazole and a MIC of 2 mg/L for voriconazole. c Repeating the MIC of anidulafungin resulted in a MIC of 0.016–0.032 mg/L for all isolates.
jof-07-00164-t002_Table 2 Table 2 Nonsynonymous mutations in azole-resistant A. flavus isolates compared to two isogenic azole-susceptible isolates.
Amino Acid Change
Chr.-Pos. a Allele Isolate b A. oryzae Gene c (RefSeq Accession Numbers) A. flavus Gene d Function
3 4 5 6 7 8 9 10 11
1-498965 T A I997N I997N I997N I997N I997N AO090009000185 (XM_001816630) AFLA_052710 GTPase activating protein
1-561401 A G R52G AO090009000208 (XM_023234211) AFLA_052490 unknown
1-1099800 C T A221T A221T A221T A221T AO090009000417 (XM_001816830) AFLA_050600 Aldehyde dehydrogenase
1-3360498 T C V99A AO090005001154 (XM_023232984) AFLA_083950 MSF transporter
1-3370761 T A H25Q H25Q H25Q H25Q H25Q H25Q AO090005001151 (XM_023232999) AFLA_083930 DnaJ domain protein
2-578295 C T P38L P38L P38L P38L P38L AO090001000237 (XM_001818728) Global gene regulator VeA
2-579927 G A A561T AO090001000237 (XM_001818728) Global gene regulator VeA
2-2642838 T A Y119F Y119F Y119F Y119F Y119F Y119F Y119F Y119F AO090003000205 (XM_001819367) AFLA_036130 14-alpha sterol demethylase
2-3253116 T C K1757R K1757R K1757R K1757R K1757R K1757R AO090003000437 (XM_001819566) AFLA_033810 NPC protein An-Mlp1
3-851374 A G I570T I570T I570T I570T I570T I570T AO090023000332 (XM_023235544) AFLA_107440 Sla1
4-1887254 C T T159I AO090012000739 (XM_023236608) unknown
4-4726184 C T R669Q R669Q R669Q R669Q R669Q AO090166000062 (XM_023237067) unknown
7-2588623 C A E35* E35* E35* E35* E35* E35* AO090206000001 (XM_023233185) AFLA_115530 C-4 methylsterol oxidase
8-891870 G A P445L AO090103000145 (XM_023233427) AFLA_010830 unknown
Mutations are described based on mapping to the A. oryzae RIB40 reference genome. A. flavus equivalent genes are indicated. a Mutations are indicated by the chromosome number and nucleotide position in the A. oryzae RIB40 reference genome. b Subsequent isolates are indicated by their numbers: 3: V156-58, 4: V158-11, 5: V158-20, 6: V158-70, 7: V158-75, 8: V158-76, 9: V158-77, 10: 159-40, and 11: 159-56. c Annotated gene names based on the A. oryzae RIB40 reference genome. d Annotated gene names based on from the A. flavus NRRL3357 reference genome. If no annotation was available, the row was left empty.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Visual impairment'. | Genetic and Phenotypic Characterization of in-Host Developed Azole-Resistant Aspergillus flavus Isolates.
Aspergillus flavus is a pathogenic fungal species that can cause pulmonary aspergillosis, and triazole compounds are used for the treatment of these infections. Prolonged exposure to azoles may select for compensatory mutations in the A. flavus genome, resulting in azole resistance. Here, we characterize a series of 11 isogenic A. flavus strains isolated from a patient with pulmonary aspergillosis. Over a period of three months, the initially azole-susceptible strain developed itraconazole and voriconazole resistance. Short tandem repeat analysis and whole-genome sequencing revealed the high genetic relatedness of all isolates, indicating an infection with one single isolate. In contrast, the isolates were macroscopically highly diverse, suggesting an adaptation to the environment due to (epi)genetic changes. The whole-genome sequencing of susceptible and azole-resistant strains showed a number of mutations that might be associated with azole resistance. The majority of resistant strains contain a Y119F mutation in the Cyp51A gene, which corresponds to the Y121F mutation found in A. fumigatus. One azole-resistant strain demonstrated a divergent set of mutations, including a V99A mutation in a major facilitator superfamily (MSF) multidrug transporter (AFLA 083950).
1. Introduction
Chronic pulmonary aspergillosis (CPA) is a relatively uncommon pulmonary disease, occurring in apparently nonimmunocompromised patients. The disease often affects patients with other respiratory disorders such as chronic obstructive pulmonary disease, tuberculosis, nontuberculous mycobacteria (NTM) infection, prior pneumothorax or treated lung cancers [1,2]. Aspergillus fumigatus is the causative species of CPA in the majority of patients, but other species such as A. niger, A. terreus and A. flavus may also be cultured from patients with CPA [3]. Subacute invasive aspergillosis (SAIA) is another clinical presentation of pulmonary aspergillosis occurring in mild immunocompromised patients. The clinical and radiological features are very similar to CPA, but the progression of the disease is more rapid. In contrast to CPA, serum galactomannan is often positive in SAIA. However, SAIA has a slower course of progression (one to three months) compared to acute invasive aspergillosis [1]. Symptomatic or progressive CPA is treated primarily with itraconazole, but voriconazole and posaconazole are potential alternative agents [1,4]. Patients with SAIA should always be treated with antifungals according to the CPA guideline. Voriconazole and isavuconazole are regarded as first-line agents for these patients [1,4].
Azole resistance in A. fumigatus is reported in many countries worldwide and challenges the treatment of Aspergillus diseases [5,6]. Although azole resistance has also been described in A. flavus isolates, the mechanism of azole resistance has been less extensively studied in A. flavus compared to A. fumigatus. Azole-resistant infections may be due to the direct inhalation of resistant spores present in the environment. Alternatively, azole resistance may develop during azole treatment, characterized by a phenotype switch from drug susceptible to drug resistant [7,8]. The latter occurs primarily in patients with chronic forms of aspergillosis receiving long-term therapy and especially in those with pulmonary cavities [9,10].
Here, we describe a patient who was treated for SAIA. During antifungal treatment, several A. flavus isolates were cultured. The sequentially cultured isogenic isolates in this study showed a highly variable macroscopic morphology. The first two isolates appeared to be azole susceptible, and the following nine isolates had increased MICs for voriconazole and itraconazole. Azole resistance generally comes with a fitness cost, which may become apparent through growth variation when resistant isolates are cultured in the absence of azole pressure under laboratory conditions [11]. In A. fumigatus, similar variations in colony morphology were observed in sequential cultures [12]. To further understand in-host adaptation dynamics of A. flavus during antifungal treatment, we performed genetic analysis of 11 cultured A. flavus isolates from consecutive cultures obtained from a single patient during azole treatment for SAIA.
2. Materials and Methods
2.1. Origin of Strains and Antifungal Treatment
The 11 strains used in this study were cultured from a 66-year-old female with COPD Gold IIA. One and a half years prior to the first A. flavus culture, computed tomography (CT) of the lungs showed a cavity, and subsequent biopsy culture showed Mycobacterium intracellulare, which was treated with clarithromycin. Eight months later, CT showed an aspergilloma in the pre-existing cavity, and the patient was treated with voriconazole for six weeks. As the patient’s condition worsened, with progressive weight loss and recurrent hemoptysis, she was referred to the University Medical Centre (Nijmegen, the Netherlands) for the optimization of nontuberculosis mycobacterial treatment. Her antimycobacterial therapy was changed to clarithromycin, rifampicin and ethambutol. No clinical improvement was observed, and two sputum cultures showed A. flavus (Isolates 1 and 2), which prompted a diagnostic work-up for CPA (Figure 1 and Figure 2). The serum galactomannan (GM) index (2.0), Aspergillus IgG (43 mg/L) (ImmunoCap) and IgE antibodies (0.44 kU/L) were positive, which, together with her CT scan abnormalities, were consistent with SAIA. Antifungal treatment was again started with liposomal amphotericin B (L-AmB). Although A. flavus may be less susceptible to L-AmB treatment, the concurrent use of rifampicin precluded azole therapy, and L-AmB was chosen as the second-best option. After six weeks, both L-AmB and rifampicin were stopped due to side effects. The serum GM index had declined to 0.6. The patient was subsequently treated with voriconazole, which was changed to itraconazole after two weeks due to visual disturbances. During this therapy, A. flavus was cultured from sputum, which now showed an azole-resistant phenotype (Isolate 3), and antifungal treatment was changed to anidulafungin. In addition, terbinafine was started as the terbinafine MICs were low, and the combination was aimed to prevent or delay further resistance selection. As symptoms worsened and serum GM increased to 3, L-AmB was restarted after five weeks. As no improvement was observed despite continued antifungal and tuberculostatic agents, antifungal treatment was stopped, and the patient was discharged. The patient remained stable for some time after discharge but eventually died after 12 months.
Over a six-month period, 11 isolates were cultured from the patient, and all were morphologically identified as A. flavus at the Centre of Expertise in Mycology Radboudumc/CWZ. Isolates were stored at −80 ℃ in 10% glycerol. In vitro susceptibility testing of the isolates was performed according to the EUCAST broth microdilution reference method for molds (E.def 9.2) [13]. Isolates were tested at a final drug concentration range of 0.032–16 mg/L for itraconazole, voriconazole and posaconazole. The endpoint defined as no growth was visually determined. Susceptibility testing was performed at the time the isolates were cultured, and the results were confirmed by reviving the isolates and repeating the susceptibility testing. Short tandem repeat (STR) typing was performed as described previously using three sets of three markers (AflaSTR2, AflaSTR3 and AflaSTR4) [14,15]. The isolates were phenotyped by studying the colony morphology on agar media (creatine agar (CREA), Czapek yeast extract agar (CYA) incubated at 25, 37 and 40 °C, CYA supplemented with 5% NaCl (CYAS), dichloran 18% glycerol agar (DG18), malt extract agar (MEA), Sabouraud dextrose agar (SAB) and yeast extract sucrose (YES) agar). The agar media were inoculated in a three-point position and incubated for 7 days at 25 °C (unless stated otherwise) in darkness. The composition of the media is according to Samson et al. [16]. Partial β-tubulin (BenA), calmodulin (CaM) and RNA polymerase II second largest subunit (RPB2) sequencing were performed as previously described [17].
2.2. Whole-Genome Sequencing and Analysis
Genomic DNA was extracted from conidia. Conidia were suspended in Tris–EDTA buffer (pH 8, supplemented with 1% SDS, 2% Triton × 100 and 100 mM NaCl). The suspension was shaken for 30 min at 70 °C. DNA was extracted using phenol/chloroform and purified using the QIAamp DNA Blood Mini kit (Qiagen, Aarhus, Denmark). A fragmented genomic DNA library was prepared using a Nextera XT DNA sample preparation kit (Illumina, San Diego, USA). Subsequent sequencing was conducted in a paired-end 2 × 150 bp mode using an Illumina NextSeq500 machine. Reads were mapped to the Aspergillus flavus NRRL3357 (Assembly GCA_000006275.2, EnsemblFungi) and Aspergillus oryzae RIB40 (ASM18445v3) (Assembly GCA_000184455.3, EnsemblFungi) reference genomes using CLC Genomics Workbench 12 (Qiagen, Aarhus, Denmark). Single-nucleotide polymorphism (SNP) detection and variant comparisons were conducted using CLC Genomics Workbench 12 (Qiagen) and the Basic Variant Detection method with ploidy 1, a minimum coverage of 5 and a minimum probability of 0.8.
Whole-genome sequencing data from 14 A, flavus and A. oryzae strains were obtained from the NCBI SRA database (Appendix A Table A1). Contigs were generated by de novo assembly using sequencing reads from all clinical samples and reference strains. Whole-genome alignment was performed on sets of contigs with a minimum size of 10 kb. Whole-genome alignment and pairwise comparison were performed using the Whole-Genome Alignment tool implemented in CLC Genomic Workbench version 20.0.4 with default settings [18]. The generated distance matrix, based on the average nucleotide identity (ANI), was used to calculate the neighbor-joining phylogenetic relationships (Figure 3).
SNP-calling on the various clinical samples was done by mapping reads of individual strains to contigs obtained from strain V159-40 as a reference genome. Variants were determined by the Basic Variant Detection tool in CLC Genomics Workbench version 20. The ploidy number was set to one and the minimum frequency filter to 95%. Default values were used for all other parameters and variant filters. Sequences containing SNPs present in a total of 177 positions were aligned using MAFFT [19]. A maximum-likelihood phylogenetic tree was calculated using CLC Genomics Workbench version 20.
3. Results
3.1. Strains, Phenotypical Analysis and Genotyping
Partial BenA, CaM and RPB2 sequencing confirmed the morphological species identification as A. flavus. All isolates had identical BenA, CaM and RPB2 sequences. The results of the susceptibility testing are shown in Table 1. Isolates 1 and 2 had low MICs for the azoles, and the azole MICs of Isolates 3–11 were increased compared to Isolates 1 and 2. Repeated testing of isolates showed similar MICs (within two dilution steps) for all isolates, except Isolate 4. For Isolate 4, the increased MICs could not be reproduced, even after subculturing the isolate on azole-containing agar first. The MIC of amphotericin B was either 1 or 2 mg/L for all isolates, and the MIC of anidulafungin ranged from 0.016 to 0.025 mg/L (Table 1).
Growth analysis of the isolates at eight different conditions revealed a diverse colony morphology (Figure 4 and Figure A1), and none of the isolates were phenotypically identical. Isolates 1 and 2 showed typical spreading A. flavus colonies, with abundant sclerotia production on CYA incubated at 25 °C and yellow-green-colored conidia. Isolate 5 resembled Isolates 1 and 2, though sporulation was absent on most agar media, and growth was reduced on DG18. Isolates 3, 6, 8 and 11 had similar colony diameters, and of those isolates, 6 and 11 had a similar degree of sporulation. Compared to Isolates 1 and 2, these isolates had smaller colony diameters on CYAS and DG18. Isolate 4 was unique in producing greenish-brown-colored conidia, and Isolate 9 had very restricted growth, unlike all other isolates. Isolates 7 and 10 resembled each other in colony diameters, though Isolate 7 sporulated more strongly. Short tandem repeat genotyping revealed full genetic relatedness between all isolates, suggesting that the isolates originate from the same parent strain. The tandem repeat numbers are shown in Table 1.
3.2. Whole-Genome Sequence Analysis
Aspergillus flavus NRRL3357 and A. oryzae RIB40 were used as reference genomes for read mapping based on an assessment of mapping quality and coverage statistics; a mean coverage of approximately 40 and a mean mapping quality score of 40 were found across the sequenced isolates. A total of 31 nonsynonymous SNPs, absent in early Isolates 1 and 2, were identified in later isolates (Table 2). The cyp51A mutation Y119F (corresponding to the Y121F mutation in A. fumigatus) was found in Isolates 3 and 5-11 but not in Isolate 4. Isolates 3, 5, 6, 8, 9 and 11 had a mutation in a gene with putative C-4 methyl sterol oxidase function, resulting in a stop codon at Locus 35. Isolate 4 did have a point mutation in a putative major facilitator superfamily (MFS) transporter (AFLA_083950). Phylogenetic relationship analysis based on whole-genome sequencing data confirmed the results based on short tandem repeat genotyping. All sequential cultured strains showed a genetic relationship (Figure 3). Phylogenetic relationship analyses of the 11 cultured A. flavus strain showed that Isolates 2, 7 and 10 were genetically highly similar to each other. Isolates 3, 6, 8, 9 and 11 were more genetically related to each other (Figure A2).
4. Discussion
Here, we describe the characteristics of 11 A. flavus isolates that were cultured during the treatment of SAIA in a patient with chronic lung disease. All isolates were identified as A. flavus and had identical partial BenA, CaM and RPB2 gene sequences, showing high genetic similarity. STR analysis and whole-genome sequencing further confirmed the isogeneity of all isolates. The isolates were macroscopically very diverse and later isolates showed decreased in vitro susceptibility to azoles.
Azole resistance is an increasing problem worldwide, especially in A. fumigatus. [20]. However, reports on azole resistance in A. flavus are sparse, and the resistance mechanisms are generally unknown. Several single-nucleotide polymorphisms (SNPs) have been reported in the A. flavus Cyp51 genes encoding lanosterol 14 alpha-demethylase. This protein is the target of azoles, and the A. flavus genome contains three orthologs of this gene. One study demonstrated S196F, A324P, N423D and V465M polymorphisms in the Cyp51C gene in an azole-resistant isolate [21]. However, another study identified the same SNPs in both azole-susceptible and azole-resistant isolates, arguing against the association of these mutations for azole resistance [22]. Another study suggested the role of the S240A SNP in the Cyp51C gene. They found an S240A SNP in an isolate with increased voriconazole MICs and confirmed its role in voriconazole tolerance by transformations [23]. However, again, this SNP was also found in many azole-susceptible isolates [21,22,24]. The last SNP in Cyp51C that was suggested to play a role in azole susceptibility is Y319H [24]. In laboratory-selected resistant isolates using voriconazole stress, both Cyp51A and Cyp51B mutations were identified compared to the parental strain. K197N, Y132N+T469S and K197N+D282E+M288L SNPs were found in the Cyp51A of isolates with increased voriconazole MICs, and H399P+D411N and T454P+T486P were observed in the Cyp51B of 2 other isolates [25]. However, a direct relationship with azole resistance was not established. In addition, other non-cyp51-mediated mechanisms, such as azole efflux, due to the overexpression of ATP-binding cassettes (ABC) and MFS transporters, have been suggested to play a role in azole resistance in A. flavus. [26].
We identified a novel Y119F substitution in the cyp51A gene, which seemed to be the cause of the azole resistance phenotype in eight of nine azole-resistant isolates. Although the relation of the Y119F mutations and azole resistance is not formally proven, strong indirect evidence is available. First, the mutation was observed in azole-resistant strains, and the genetically identical parental isolates without this mutation were susceptible. Secondly, in A. fumigatus, the homolog Y121F mutation is directly linked to increased voriconazole MICs, and this phenotype is supported by a CYP51A homology protein model [27,28]. Furthermore, Y119F-corresponding homologous mutations in other fungal species have similar effects on azole susceptibility. For example, the homolog Y132F mutation has been described in azole-resistant Candida albicans and was also found in azole-resistant C. auris and C. parapsilosis isolates [29,30,31]. The homolog Y145F mutation in C. neoformans [32] and the Y136F mutation in the Histoplasma capsulatum cyp51A gene [33] were associated with reduced voriconazole susceptibility. Furthermore, the homolog Y137F mutation in Mycosphaerella graminicola [34] and the Y136F mutation in Uncinula necator [35] are associated with resistance to triadimenol, a triazole that shows structurally more resemblance to voriconazole than to the long-tailed triazole itraconazole and posaconazole. Interestingly, the C. neoformans and H. capsulatum strains with Y145F and Y136F mutations remained susceptible to itraconazole and posaconazole [32,33]. Thus, the increased MICs of voriconazole observed in our isolates are likely explained by the Y119F mutation in the Cyp51A gene. However, itraconazole showed paradoxical growth (eagle effect) in our clinical isolates, where significant growth inhibition was seen at relatively low concentration but only minimal growth inhibition at higher concentrations of itraconazole. Whether the Y119F substitution is causing this phenomenon and whether itraconazole remains clinical effective is not clarified.
Another mutation resulting in a stop codon at Locus 35 found in six of nine azole-resistant isolates might also be involved in adaptation to azole stress. Orthologs of the AFLA_115530 gene, which has a putative C-4 methyl sterol oxidase function, are involved in sterol biosynthesis. The orthologs ERG25 and ERG25b in A. fumigatus are upregulated during azole stress [36]. Furthermore, in vitro itraconazole selection was pressure-selected for a mutation in the ERG25 gene of A. fumigatus. [37]. Although the precise function and its effect on azole susceptibility are largely unknown, azole stress may have resulted in the selection of this mutation. In addition to azole treatment, the patient was treated with L-AmB and anidulafungin, which may select for mutations in the ERG genes or FKS gene. However, none of the isolates had increased L-AmB MICs and SNPs in the FKS gene were not identified.
Isolate 4 did not harbor the Y119F Cyp51A mutation or the mutation putative C-4 methyl sterol oxidase. Initial testing showed increased MICs for itraconazole and voriconazole, but after reviving the stored isolate, repeated testing could not confirm the initially observed phenotype. It could be that this isolate harbored a nonstable resistance mechanism that was lost during storage and subculturing. However, growing the isolate under azole pressure did not reproduce the increased MICs (data not shown). Alternatively, the stored isolate might not have been a pure culture, and reviving and subculturing may have resulted in the selection of a faster-growing nonresistant isolate. Whole-genome sequencing revealed a mutation in the putative MFS transporter (AFLA_083950) gene of this isolate. In A. fumigatus, azole stress increases the expression of the ortholog AFU1G15490 gene, and thus this gene may be involved in the development of azole tolerance [38]. However, further studies would be required to confirm this observation.
Isolates 3, 5, 6, 8 and 11 share a similar mutation pattern and also have similar growth rates (Table A2). Compared to isolates 1 and 2 (wild-type phenotype), all strains grow slower on DG18 and, with the exception of Isolate 5, slower on CYAS (Figure 4). These two agar media have a lowered water activity due to the presence of glycerol (DG18) and NaCl (CYAS). It can be speculated that the evolution of the isolate in the patient led to reduced stress resistance against lowered water activity, a condition not present in the human lung. In contrast, A. fumigatus isolates obtained from humans with suspected invasive pulmonary aspergillosis and dogs with sino-orbital aspergillosis have a higher growth rate on DG18 compared with environmental strains [39]. Isolate 4 has four mutations (R52G, V99A, A561T, T159I) that are not observed in the other isolates. The production of greenish-brown-colored conidia is a unique macro-morphological feature of this isolate and might be linked to one or a combination of these mutations. The function of two genes with mutations is unknown; the other two are an MSF transporter and a global gene regulator VeA. Isolates 7 and 10 resemble each other and these two strains only have the Y119F mutation. These strains have similar growth rates as Isolates 1 and 2 but lack the production of sclerotia and acid production on CREA.
Phylogenetic analysis of the isolates showed that Isolates 2, 7 and 10 were highly similar, indicating these isolates were from the same subpopulation. Isolate 2 was isolated at the beginning of the infections, whereas Isolate 10 was cultured six months later. However, several less-related A. flavus isolates were cultured between Isolates 2 and 10, which possibly represent different subpopulations in the lungs of the patient. This indicates that the patient was initially infected with a single A. flavus strain, which resulted in several subpopulations. Furthermore, it also indicates that these subpopulations of A. flavus were present in the lungs of the patient at the same time. The first azole-resistant isolates were cultured already after one week of voriconazole treatment. It could be that the resistant isolates acquired the resistance-associated mutations during the earlier six weeks’ voriconazole treatment and thus were already present in the lung of the patient. It could be that these resistant isolates were selected during the second treatment with voriconazole. This would explain how the resistant strains could be isolated after a very short course of voriconazole treatment. The clinical samples did not grow strains from every population in every culture that was taken from this patient. Thus, even when a culture from a patient with aspergillosis is positive, it could be that another isogenic population of Aspergillus is present in the lung with a different susceptibility phenotype if SNPs conferring resistance were selected in this subpopulation. Accordingly, as not all subpopulations will be detected in a single culture, patients with CPA treated with antifungal agents should be cultured repeatedly, especially if a pulmonary cavity is present in the lungs or the patient does not improve clinically.
The sequentially cultured isolates in this study were morphologically very diverse. Interestingly, STR and genomic analysis showed that all isolates were isogenic, indicating that the patient was infected with one single isolate. Only few SNPs were found in later isolates compared to the first two cultured isolates. The variable colony morphology may be due to fitness costs associated with resistance development, nutrient availability or adaptation to other host stressors [9,40]. In vitro studies indicate that azole stress may result in morphological variation. The in vitro selection of azole resistance using posaconazole resulted in apparent morphological changes in A. fumigatus colonies [41]. Similar morphological changes were observed in azole-resistant isolates exposed to itraconazole selection pressure [11]. Morphological variation was also seen in consecutive A. fumigatus isolates cultured from a patient with recurrent invasive aspergillosis extensively treated with several antifungals [12]. It is possible that the observed mutations in our isolates underlie the variable phenotypes, but other underlying (epi)genetic mechanisms may be undiscovered. The precise role of the mutations observed in our study regarding the morphological variation remains unknown and could not be explained by the function of the mutated genes alone. Further transformation studies would be needed to further elaborate on the role of these genes. Our observations show that genetically related isolates can be very different morphologically, and genetic relatedness cannot be excluded based on morphology alone [42].
Author Contributions
Conceptualization, P.E.V. and W.J.G.M.; validation, J.B.B. and J.Z.; formal analysis, J.B.B., J.F.M., J.H. and J.Z.; writing—original draft preparation, J.B.B. and J.H.; writing—review and editing, M.H.R., J.Z., M.S., J.F.M., P.E.V. and W.J.G.M.; supervision, P.E.V. and W.J.G.M. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Informed Consent Statement
Patient consent was waived as the patients was deceased.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article.
Conflicts of Interest
The authors declare no conflict of interest.
Appendix A
Figure A1 Overview of the phenotypic diversity of A. flavus isolates (all reverse, 7 days at 25 °C, unless stated otherwise). Columns, left to right: CYA, CYA incubated 37 °C, CYA incubated 40 °C, CYAS, YES, MEA, CREA, DG18, SAB. Rows, top to bottom: Isolates 1–11.
Figure A2 Maximum-likelihood phylogenetic tree of the 11 A. flavus isolates.
jof-07-00164-t0A1_Table A1 Table A1 Strain information including accession numbers of the strains used for phylogenetic analysis based on whole-genome sequencing data.
Accession Number Organism Strain Origin
1 SRR4142427 A. flavus 3357 wt parent Unknown USA
2 SRR5906257 A. flavus WRRL1519 Almond nut Cal. USA
3 SRR6914138 A. flavus ATCC200026 Peanut USA
4 SRR7615260 A. flavus NRRL21882 Peanut USA
5 SRR8554744 A. flavus from corn (Miss. USA) Corn Miss. USA
6 SRR8556699 A. flavus from corn (Miss. USA) Corn Miss. USA
7 SRR11596600 A. flavus 07-S-2-5-7 Corn Louis. USA
8 SRR11596612 A. flavus 07-S-2-5-4 Corn Louis. USA
9 SRR12001143 A. flavus TX-B-1-1-1 Soil USA
10 SRR12001155 A. flavus PA-B-20-3-1 Soil USA
12 SRR7615261 A. oryzae M2040 Industrial strain South Korea
13 SRR1835311 A. oryzae RIB40 Industrial strain unknown
15 DRR163532 A. oryzae TK-82 replicate 2 Industrial strain unknown
16 DRR163631 A. oryzae TK-82 replicate 1 Industrial strain unknown
17 SAMN14278081 A. flavus V152-39 Clinical sample The Netherlands
18 SAMN14278082 A. flavus V152-49 Clinical sample The Netherlands
19 SAMN14278083 A. flavus V156-58 Clinical sample The Netherlands
20 SAMN14278084 A. flavus V158-11 Clinical sample The Netherlands
21 SAMN14278085 A. flavus V158-20 Clinical sample The Netherlands
22 SAMN14278086 A. flavus V158-70 Clinical sample The Netherlands
23 SAMN14278087 A. flavus V158-75 Clinical sample The Netherlands
24 SAMN14278088 A. flavus V158-76 Clinical sample The Netherlands
25 SAMN14278089 A. flavus V158-77 Clinical sample The Netherlands
26 SAMN14278090 A. flavus V159-40 Clinical sample The Netherlands
27 SAMN14278091 A. flavus V159-56 Clinical sample The Netherlands
jof-07-00164-t0A2_Table A2 Table A2 Overview of the amino acid changes of nine A. flavus isolates and the unique macromorphological characteristics.
Isolate Amino Acid Change Colony Diameter (mm, after 7 d, 25 °C) Unique Macromorphological Characters Compared to Isolates 1–2 a
I997N R52G A221T V99A H25Q P38L A561T Y119F K1757R I570T T159I R669Q E35* P445L CYAS DG18
3 x x x x x x x x x x 36–38 32–34 Colony diameters smaller on DG18 and CYAS, sporulation variable
4 x x x x 50–53 >60 Colony diameters slightly smaller on CYAS; greenish-brown-colored conidia
5 x x x x x x x x 54–58 36–38 Colony diameters smaller on DG18, slightly smaller on CYAS; sporulation generally absent or weak
6 x x x x x x x x x 26–30 32–34 Colony diameters smaller on DG18 and CYAS; sporulation variable
7 x >60 >60 Colony diameters similar as Isolates 1–2; abundant sporulation on all agar media, except creatine agar
8 x x x x x x x x x 36–38 29–32 Colony diameters smaller on DG18 and CYAS; sporulation variable
9 x x x x x x 8–10 16–18 Colony diameters restricted on all agar media; sporulation absent
10 x 54–58 >60 Growth diameters slightly smaller on CYAS, sporulation generally moderate or good
11 x x x x x x x x 35–38 30–33 Colony diameters smaller on DG18 and CYAS; sporulation variable
a Isolates 3–11 are compared to isolates 1 and 2; the latter two isolates present a typical A. flavus phenotype with a high growth rate on most media (CYAS: >60 mm, DG18: >60 mm), production of yellow-green-colored conidia and black sclerotia. Isolates 3–11 do not produce sclerotia or acid on creatine agar.
Figure 1 Chest computed tomography image showing a large pulmonary cavity in the left upper lobe with a mass lying in the cavity.
Figure 2 Timeline of the antifungal treatment and A. flavus culture morphology. VCZ, voriconazole; ICZ, itraconazole; L-AMB, liposomal amphotericin B; TRB, terbinafine; ANI, anidulafungin. The dates that clinical samples were obtained from the patient are indicated in the Figure, and the numbering of the isolates is based on the date the cultures became positive. Isolates 7 and 9 were cultured from the same clinical material but showed different morphologies. Isolate 8 was cultured from a clinical sample obtained 2 days after Isolates 7 and 9. This culture was earlier positive than the cultures of Isolate 9.2.2. Strains, phenotypic analysis, antifungal susceptibility and typing.
Figure 3 Neighbor-joining phylogenetic relationships of sequential isolated A. flavus strains and 14 A. flavus and A. oryzae strains obtained from the NCBI SRA database based on whole-genome sequencing data. The phylogenetic relationship was calculated from a distance matrix based on the average nucleotide identity.
Figure 4 Overview of the phenotypic diversity of A. flavus isolates (all obverse, 7 days at 25 °C, unless stated otherwise). Columns, left to right: Czapek yeast extract agar (CYA), CYA incubated 37 °C, CYA incubated 40 °C, CYA supplemented with 5% NaCl (CYAS), yeast extract sucrose (YES), malt extract agar (MEA), creatine agar (CREA), dichloran 18% glycerol agar (DG18), Sabouraud dextrose agar (SAB). Rows, top to bottom: Isolates 1–11.
jof-07-00164-t001_Table 1 Table 1 Overview susceptibility and short tandem repeat (STR) typing of 11 sequentially cultured A. flavus isolates MIC minimal inhibitory concentration.
Strain Number Isolation Date MIC (mg/L) STR Numbers
ITC VOR POSA AMB ANI c 2 3 4
1 V152-39 8-8-2013 0.5 1 0.5 1 0.063 23-14-17 8-22-12 5-7-2011
2 V152-49 12-8-2013 1 4 0.25 2 0.031 23-14-17 8-22-12 5-7-2011
3 V156-58 22-11-2013 16 a >16 0.5 2 0.031 23-14-17 8-22-12 5-7-2011
4 V158-11 31-12-2013 >16 a,b >16 b 1 2 0.063 23-14-17 8-22-12 5-7-2011
5 V158-20 3-1-2014 16 a 16 0.5 1 0.016 23-14-17 8-22-12 5-7-2011
6 V158-70 17-1-2014 2 >16 0.5 2 0.016 23-14-17 8-22-12 5-7-2011
7 V158-75 21-1-2014 >16 a >16 1 2 0.125 23-14-17 8-22-12 5-7-2011
8 V158-76 23-1-2014 >16 a >16 1 2 0.125 23-14-17 8-22-12 5-7-2011
9 V158-77 21-1-2014 1 16 0.25 2 0.25 23-14-17 8-22-12 5-7-2011
10 V159-40 3-2-2014 >16 a >16 2 2 0.031 23-14-17 8-22-12 5-7-2011
11 V159-56 7-2-2014 1 >16 0.5 2 0.016 24-14-17 8-22-12 5-7-2011
STR, short tandem repeats; ITC, itraconazole; VOR, voriconazole; POSA, posaconazole; AMB, amphotericin B; ANI, anidulafungin. a Isolates showed paradoxical growth (eagle effect). Significant growth inhibition was seen at a relatively low concentration but only minimal growth inhibition at higher concentrations of itraconazole. b The MIC results could not be reproduced. Repeated testing showed a MIC of 0.25 mg/L for itraconazole and a MIC of 2 mg/L for voriconazole. c Repeating the MIC of anidulafungin resulted in a MIC of 0.016–0.032 mg/L for all isolates.
jof-07-00164-t002_Table 2 Table 2 Nonsynonymous mutations in azole-resistant A. flavus isolates compared to two isogenic azole-susceptible isolates.
Amino Acid Change
Chr.-Pos. a Allele Isolate b A. oryzae Gene c (RefSeq Accession Numbers) A. flavus Gene d Function
3 4 5 6 7 8 9 10 11
1-498965 T A I997N I997N I997N I997N I997N AO090009000185 (XM_001816630) AFLA_052710 GTPase activating protein
1-561401 A G R52G AO090009000208 (XM_023234211) AFLA_052490 unknown
1-1099800 C T A221T A221T A221T A221T AO090009000417 (XM_001816830) AFLA_050600 Aldehyde dehydrogenase
1-3360498 T C V99A AO090005001154 (XM_023232984) AFLA_083950 MSF transporter
1-3370761 T A H25Q H25Q H25Q H25Q H25Q H25Q AO090005001151 (XM_023232999) AFLA_083930 DnaJ domain protein
2-578295 C T P38L P38L P38L P38L P38L AO090001000237 (XM_001818728) Global gene regulator VeA
2-579927 G A A561T AO090001000237 (XM_001818728) Global gene regulator VeA
2-2642838 T A Y119F Y119F Y119F Y119F Y119F Y119F Y119F Y119F AO090003000205 (XM_001819367) AFLA_036130 14-alpha sterol demethylase
2-3253116 T C K1757R K1757R K1757R K1757R K1757R K1757R AO090003000437 (XM_001819566) AFLA_033810 NPC protein An-Mlp1
3-851374 A G I570T I570T I570T I570T I570T I570T AO090023000332 (XM_023235544) AFLA_107440 Sla1
4-1887254 C T T159I AO090012000739 (XM_023236608) unknown
4-4726184 C T R669Q R669Q R669Q R669Q R669Q AO090166000062 (XM_023237067) unknown
7-2588623 C A E35* E35* E35* E35* E35* E35* AO090206000001 (XM_023233185) AFLA_115530 C-4 methylsterol oxidase
8-891870 G A P445L AO090103000145 (XM_023233427) AFLA_010830 unknown
Mutations are described based on mapping to the A. oryzae RIB40 reference genome. A. flavus equivalent genes are indicated. a Mutations are indicated by the chromosome number and nucleotide position in the A. oryzae RIB40 reference genome. b Subsequent isolates are indicated by their numbers: 3: V156-58, 4: V158-11, 5: V158-20, 6: V158-70, 7: V158-75, 8: V158-76, 9: V158-77, 10: 159-40, and 11: 159-56. c Annotated gene names based on the A. oryzae RIB40 reference genome. d Annotated gene names based on from the A. flavus NRRL3357 reference genome. If no annotation was available, the row was left empty.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | VORICONAZOLE | DrugsGivenReaction | CC BY | 33668871 | 19,126,259 | 2021-02-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature.
BACKGROUND
Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy. The disease remained under control for 11 months after the first relapse.
CONCLUSIONS
In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors.
CONCLUSIONS
Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with.
1. Introduction
Over the past decade, tumor molecular profiling has been widely applied, leading to an individualized approach for patients termed “personalized” or “precision medicine”. This new approach has replaced the standard chemotherapy treatment based on the tumor’s origin, histology and nodal invasion (TNM) [1]. The aim of precision medicine is to define treatment based upon genomic drivers of tumorigenesis, thus identifying the best therapy for patients [2]. Moreover, precision oncology assesses tumor response to a specific treatment and finds drug resistance when it occurs [3].
The BRAF mutant is an oncogenic driver, since BRAF inactivation slows down systemic tumor growth and induces cancer cell toxicity [4]. BRAF is a member of the Raf kinase family and plays a critical role in cellular growth, proliferation and differentiation through the MAP-kinase (MAPK) pathway [5].
The Cancer Genome Atlas (TCGA) has identified BRAF mutations in many different cancer types: 60% of melanomas, 60% of thyroid cancers, 15% of colorectal cancers, and 5–8% of non-small cell lung cancers [6]. Moreover, mutations in this gene are present in diffuse gliomas, cholangiocarcinoma, hairy cell leukemia, multiple myeloma, Langerhans cell histiocytosis and Erdheim–Chester disease [7].
Around 200 BRAF mutant alleles and 30 mutations of BRAF have been identified and characterized and V600E is the most common mutation [8]. BRAF mutations can be classified into three classes: class 1 and 2 are RAS-independent, while class 3 depends on RAS signaling [9].
Pembrolizumab and nivolumab for patients with high levels of microsatellite instability and deficient DNA mismatch repair (dMMR), and larotectinib for tropomyosin receptor kinases (TRK), have introduced the concept of tumor type agnostic therapy [10] where genomic alterations could be used to drive tumor therapy, regardless of tumor origin [11].
On the basis of this concept, in this report we describe two case studies in which treatment decisions have been driven by next generation sequencing (NGS). The first case study is that of a 59-year-old Caucasian man with BRAF V600E mutated intrahepatic cholangiocarcinoma (ICC). Intrahepatic cholangiocarcinoma is the second most common hepatic cancer and its incidence is increasing worldwide [4]. One of its targetable alterations is a v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation. While BRAF mutations are rare in pancreato-biliary cancers, they are reported with higher frequency, about 5% of all cases, in ICC [12]. The majority of mutations occur at the V600 position, with V600E observed in 5% of cholangiocarcinoma (CCA) [13].
The second case study is that of a 50-year-old, Caucasian woman, with BRAF G466A mutated Bellini duct carcinoma (BDC). BDC is a very rare and aggressive variant of kidney carcinoma, arising from the renal medulla, possibly from the distal collecting ducts of Bellini [14]. BDC is characterized by an aggressive clinical course and an extremely poor prognosis [15]. Less than one-third of patients survive more than 2 years after diagnosis, and in most reported cases metastatic disease is present ab initio. Radical nephrectomy is generally performed, followed by medical treatments such as immunotherapy, targeted therapies or chemotherapy [16]. Given the rarity of this cancer, it has been difficult to conduct large-scale clinical trials and a specific standard treatment has not yet been established.
These clinical cases may represent a proof of concept of how identifying and targeting potential molecular drivers, such as BRAF mutations, independently of tissue origin, could provide represent therapeutic opportunities, especially for rare cancers.
2. Case Presentation
2.1. Case 1
A 59-year-old Caucasian male patient, with metabolic syndrome and type 2 diabetes, was admitted to the emergency department in January 2017 with severe hip pain, nausea and increasing discomfort. Abdominal ultrasound and computerized axial tomography showed the presence of a 6 × 9 cm hepatic nodule in the VI segment. In February 2017 the patient underwent VI hepatic segment resection and cholecystectomy. Immunohistochemistry revealed moderately differentiated CCA, positive for CK7, CK19 and CA19, and negative for CK20. The patient was diagnosed with cT2aN0M0 disease. Indication to standard follow-up was given due to the absence of resection margins and lymph node involvement. However, in September 2017, after seven months of follow-up, positron emission tomography (PET) showed hyperfixation of the ischio-pubic branch and sacro-iliac articulation. The subsequent ischio-pubic biopsy revealed cholangiocarcinoma metastasis. At this point, first line chemotherapy with cisplatin (25 mg/m2) and gemcitabine (1000 mg/m2) on day 1 and 8 every 3 weeks was administered for 6 cycles. Furthermore, palliative radiotherapy was performed on the bone metastasis (20 Gy in fraction 5). After 6 cycles of chemotherapy, CT scans showed hepatic, lung, lymphonodal and bone disease progression. In June 2018, after multidisciplinary discussion, the patient started a second line chemotherapy with oxaliplatin (130 mg/m2) on day 1 and capecitabine (1000 mg/m2) orally BID for 14 days every 3 weeks, without clinical and radiological response.
In light of tumor resistance to second line chemotherapy, primary tumor next generation sequencing was performed in January 2019, which showed the presence of a BRAF V600E mutation. Given this result, it was decided to start off-label use of vemurafenib (960 mg/day) and cobimetinib (60 mg/day). During the course of this therapy, he remained almost completely asymptomatic, with the exception of some episodes of grade 2 nausea and self-limiting skin rash, which occurred during the first month. Biochemical evaluations showed an increase in alkaline phosphatase and blood creatine phosphokinase during the first and second month, respectively. Six months after beginning targeted therapy, restaging CT scans reported a treatment response, with an additional reduction of pulmonary nodules and hepatic lesions. Furthermore, the bone lesions appeared sclerotic due to treatment response. His last CT scan was performed in September 2020 and confirmed stable disease (Figure 1). To date, the patient is still on treatment.
In addition, EORTC QLQ-C30 (a standardized quality of life questionnaire) was conducted both at the beginning of treatment and after the latest radiological evaluation, revealing a progressive improvement in physical functioning (essential abilities for maintaining independence) and role functioning (abilities for work/leisure). Moreover, the patient has gradually reduced opioid intake until complete suspension.
2.2. Case 2
In January 2015, a 50-year-old, Caucasian woman, without comorbidities, was admitted to our hospital with a painless gross hematuria lasting 3 months. Physical examination revealed a percussion pain over the left kidney region and no extrarenal manifestations were found at clinical and laboratory examinations. A kidney tumor was suspected on the basis of the urinary system ultrasonography and the finding was subsequently confirmed with a total body CT scan. The imaging revealed a 3 × 3.5 cm heterogeneous enhancing mass, in the middle pole of the left kidney, which was further compounded with multiple metastases in the retroperitoneal lymph nodes, ovaries and a 12 mm temporal lobe brain lesion without perilesional edema. The patient subsequently underwent laparoscopic nephroureterectomy.
The final pathological report showed Bellini duct carcinoma (BDC) of the left kidney, Fuhrman Nuclear Grade IV. The histological diagnosis of BDC was confirmed by positive immunohistochemical staining with UEA-1 and EMA, and negative staining with Leu-M1 [17]. According to the American Joint Committee on Cancer (AJCC) 2015 classification and TNM classification, the patient was diagnosed with a high-grade, stage 4 disease.
After multidisciplinary discussion, in February 2015, the patient started first line chemotherapy with bevacizumab (15 mg/kg) and gemcitabine (1250 mg/m2) on days 1 and 8 and platinum salt (cisplatin 80 mg/m2 or carboplatin AUC 5 mg/ml/min) every 3 weeks. After 3 cycles, she obtained a clinical response and a CT scan showed partial radiological response. At this stage, one of the ovarian metastasis was resected in order to create a patient-derived xenograft (PDX). At the end of the 5th cycle, she developed febrile neutropenia (neu < 500/mm3). In light of the hematological toxicity, the chemotherapy was stopped while maintaining bevacizumab every 3 weeks. Maintenance therapy was well tolerated. Furthermore, stereotaxic radiotherapy was performed on the brain metastasis (24 Gray in 2 fractions).
After 6 cycles of maintenance bevacizumab (December 2015), retroperitoneal lymph node disease progressed. Using the PDX mouse-derived model, we were able to perform a mutational analysis.
Genomic sequencing of the ovarian metastasis revealed a BRAF G466A mutation. Hence, a therapeutic combination of trametinib and dabrafenib was started. After one month of therapy, the patient developed pyrexia and rash treated with common medications; however, the 18F-FDG-PET/CT performed at the beginning of treatment and repeated after 4 weeks showed decreased FDG avidity in the ovary and lymph node metastases (Figure 2).
From January 2016 to December 2016 the patient showed stable disease. However, in January 2017, she was admitted to the emergency department complaining of headaches, nausea and dizziness; her performance status worsened to 3, requiring the patient to be hospitalized. Brain CT scans revealed multiple metastases in the frontal, parietal and temporal lobe bilaterally, further confirmed by MRI. After one week, the patient passed away due to widespread brain metastasis. The disease was under control for 11 months after the first relapse.
3. Discussion
In 2011, the Food and Drug Administration approved the BRAF inhibitor vemurafenib for the treatment of BRAF V600E mutant metastatic melanoma [18]. Dabrafenib, another BRAF inhibitor, obtained FDA approval in 2013 [19]. In the coBRIM trial, Larkin J et al. demonstrated that the combination of vemurafenib with the MEK inhibitor cobimetinib resulted in significant progression-free survival (PFS) improvement among patients with BRAF V600E mutated metastatic melanoma in comparison to the combination of vemurafenib with placebo [20]. More recent studies showed that combining BRAF and MEK inhibitors determines a PFS improvement from a median of 7 months to 12 months in this setting [21]. Furthermore, the combination of MEK and BRAF inhibitors can decrease the onset of resistance to treatment and side effects that arise during BRAF inhibitor monotherapy [22]. This combination reduces the incidence of skin toxicity, including cutaneous squamous carcinoma associated with BRAF inhibition [23]. In mutated cells, B-raf protein is found in its hyperactive form. Combined BRAF inhibitors block the Ras-Raf-MEK-MAPK kinase pathway, but, as it happens with monotherapy, pharmacological resistance may develop after 6–7 months of treatment. To overcome this resistance, BRAF inhibitors are used in combination with MEK inhibitors which mediate the blockade of MAPK kinase (MEK), downstream of BRAF in the MAPK pathway [24]. Beside melanoma, thyroid cancers [25] and colon cancers [26], the prevalence of a BRAF V600E mutation in other cancers is less than 5% [27]. The relatively low frequency of this mutation accounts for the lack of randomized controlled studies looking at the use of specific anti-BRAF targeted therapies in other cancers. This difficulty is even true in the case of very rare tumors such as CCA and BDC, so that tumor-specific studies are almost impossible to run. On the other hand, the lack of therapeutic options for these rare diseases provides a strong rationale for targeting putative driver mutations.
To address such paradoxes, basket trials have come to the rescue, putting together tumors with different histology, on the basis of their molecular landscapes and, more specifically, the presence of a BRAF V600E mutation [28]. Whilst this approach still has limitations, such as the small number of patients enrolled per tumor type, and therefore there is low statistical power in the studies, some important indications can be drawn from them. Hyman et al. report results from a basket trial including a total of 122 patients with BRAF V600E mutation-positive cancers [29]. The primary end point of the study was the response rate; secondary end points were progression-free survival and overall survival. As the response varied across tumor types, the authors concluded that BRAF V600E mutation is certainly targetable in many, but not all, cancers, and that perhaps the tumor site in which they develop are important in determining the degree of response to a specific targeted therapy. The study had 6 tumor cohorts plus an “all other cancers” cohort. Clinical activity, including some complete responses, was observed in NSCLC, Langerhans cell histiocytosis, anaplastic thyroid cancer, ovarian cancer and cholangiocarcinoma. Colon cancer patients did not show any response to vemurafenib single-agent therapy and even when the anti-BRAF therapy was combined with cetuximab the results were not encouraging. These patients were however heavily pretreated, having had 1 to 6 previous lines of therapy [29]. The contribution of mutated BRAF seems to change amongst tumor types, as suggested by the very heterogeneous results in terms of clinical benefit of BRAF inhibition in different cancers. For instance, this mutation alone may not sufficient to drive tumor progression in certain tumor types, such as colon cancer [30].
Thus, the question of whether all BRAF-mutated cancers are amenable to specific targeted therapy is still open. Perhaps, extremely rare tumors and orphan cancers, where proven effective treatment strategies are lacking, could benefit by even modest therapeutic activity. Cholangiocarcinoma is one of the most aggressive biliary tract malignancies [31]. After first-line therapy, no standard second-line treatment has been established yet and the outcome remains rather poor, with a 5-year overall survival rate of around 2% due to metastatic disease [32]. Data from the literature show that nearly 35% of CCA harbor potentially targetable genomic alterations and the use of molecular profiling has led to the discovery of potential disease drivers [33]. Lowery MA et al. showed that IDH1 (25%), TP53 (24%), ARID1A (21%), BAP1 (15%), KRAS (13%), PBRM1 (12%), SMAD (9%), ATM (8%), BRAF (<5%) and MSI-H (0.5%) are the most commonly mutated genes in CCA [13]. Biliary tract cancer reveals molecular heterogeneity and there is a crucial need to identify a subset of patients who can benefit from targeted therapy to be used after progression on first-line treatment gemcitabine plus cisplatin [34]. The ClarIDHy study showed that ivosidenub significantly improved PFS, with a trend towards favorable overall survival, in comparison to placebo in patients with advanced cholangiocarcinoma carrying an IDH1 mutation [35]. At ASCO GI 2019, Park et al. presented encouraging preliminary results on the efficacy of erdafitinib in FGFR-mutated CCA patients as a second-line therapy (NCT 02699606). Andersen et al. reported that BRAF V600E occurs with the highest frequency in ICC (1.5%) and is associated with poor prognosis [36]. Focusing on biliary tract cancer, preliminary data from the ROAR basket trial demonstrated promising activity of dabrafenib plus trametinib with a favorable safety profile in patients with BRAF V600E (ROAR trial; NCT 02034110).
Based on all these results, we decided to administer a combination of MEK and BRAF inhibitors in a patient with BRAF mutant, chemotherapy-refractory ICC and obtained results in line with the few cases reported in literature. Lavingia et al. described two cases reaching 9 and 12 months PFS when treated with dabrafenib and trametinib [37]. Bunyatov et al. showed the longest remission with the same combination: a full response after 7 months of treatment with complete remission lasting 28 months [38]. In the second case, the PDX model predicted clinical response to dabrafenib and trametinib. BDC is a rare subtype of renal cell carcinoma with an extremely poor prognosis. Given the rarity of BDC and therefore the scarcity of specific clinical trials, the best treatment for this tumor remains uncertain. The only combination of cytotoxic agents which shows effectiveness is gemcitabine plus platinum [39]. Oudard et al. showed a 26% objective response in BDC with the gemcitabine plus platinum salt regimen used as a first-line treatment [40]. Furthermore, recent data also suggest a role for anti-angiogenic therapy in this setting. Péchuchet et al. demonstrated that addition of bevacizumab to platinum-based chemotherapy in previously untreated BDC patients resulted in longer PFS and OS, with a manageable safety profile [41]. In his BDC case report, El Mehdi Tazi et al. demonstrated a therapeutic response to sunitinib [42] and Ansari J et al. showed similar results with sorafenib [43]. Unfortunately, clinical trials failed to show activity of any targeted drugs [44]. Sharing common morphological and biological characteristics with urothelial carcinomas, to date, chemotherapy remains the standard treatment for patients with BDC. Nevertheless, after progression with first-line chemotherapy, the second-line approach still presents a challenge, and patient outcome remains poor. For this reason and on the basis of the genomic sequencing results, with the presence of a BRAF G466A mutation, we decided to use the combination of anti-BRAF and anti-MEK treatment. G466A belongs to Class 3 BRAF mutations depending on RAS signaling: thus, blocking RAS signaling would appear to be a potential therapeutic strategy for class 3 BRAF-mutant tumors, but to date there are no specific inhibitors available [45].
4. Conclusions
In the last few years, there have been increasing efforts to understand the molecular biology of several rare tumors with limited treatment options. Genome analysis could, in these cases, help find specific genomic alterations which can be targeted. Precision medicine allows a personalized approach based on biomarker individualization [46].
The approval of the first-in-class tumor agnostic therapies shows that identification of biomarkers independent from tumor origin could offer new treatment options with drugs already on the market [47].
In the literature, there is strong evidence that different tumors with BRAF mutations are good targets for BRAF/MEK pathway inhibitors and our work adds to this evidence.
This report highlights the importance of molecular profiling for the management of solid tumors, and more specifically, orphan tumors. In the era of precision medicine, patients with otherwise very grim expectations can benefit from such approaches while we wait for more prospective studies to provide evidence.
Acknowledgments
The authors express sincerest gratitude to the two patients and their families, the medical staff of doctors, nurses, scientists, health and administrative personnel for the strenuous work in such a delicate moment for healthcare.
Author Contributions
Conceptualization, D.G.; investigation, O.B., C.S., M.M., and D.G.; resources, M.R.C., G.F., N.Z., V.C. and A.M.; data curation, O.B. and M.S.; writing—original draft preparation, O.B. an M.S.; writing—review and editing, S.P.C. and G.R.; supervision, D.G.; project administration, D.G.; funding acquisition, D.G. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by MEDnoTE srl (Spin-off—University of Trieste).
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of ATS Val Padana (protocol code 42998 approved on 21 december 2018).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Data is available from the authors upon request.
Conflicts of Interest
DG reports personal fees for consulting, advisory role and speakers’ bureau from Novartis, Pfizer, Lilly; fees for travel and accommodations from Novartis, Pfizer, Lilly. Other authors have no potential conflicts of interest to disclose.
Ethical Approval and Consent to Participate
All patients signed the informed consent related to the Mozart protocol. We obtained the Local Ethics Committee Val Padana approval related to the Mozart protocol (code 42998) on the 21 December 2018. The Mozart protocol is a program to understand the molecular aberrations related resistance/responsiveness to novel drugs in metastatic solid tumors.
Figure 1 (a) CT scan, March 2019; (b) CT scan, September 2020.
Figure 2 FDG-PET after 4 weeks of treatment with dabrafenib and trametinib showed decreased FDG avidity. (a) FDG-PET performed in January; (b) FDG-PET performed in February 2016.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BEVACIZUMAB, CARBOPLATIN, CISPLATIN, DABRAFENIB, GEMCITABINE, TRAMETINIB | DrugsGivenReaction | CC BY | 33669326 | 19,926,457 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash'. | Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature.
BACKGROUND
Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy. The disease remained under control for 11 months after the first relapse.
CONCLUSIONS
In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors.
CONCLUSIONS
Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with.
1. Introduction
Over the past decade, tumor molecular profiling has been widely applied, leading to an individualized approach for patients termed “personalized” or “precision medicine”. This new approach has replaced the standard chemotherapy treatment based on the tumor’s origin, histology and nodal invasion (TNM) [1]. The aim of precision medicine is to define treatment based upon genomic drivers of tumorigenesis, thus identifying the best therapy for patients [2]. Moreover, precision oncology assesses tumor response to a specific treatment and finds drug resistance when it occurs [3].
The BRAF mutant is an oncogenic driver, since BRAF inactivation slows down systemic tumor growth and induces cancer cell toxicity [4]. BRAF is a member of the Raf kinase family and plays a critical role in cellular growth, proliferation and differentiation through the MAP-kinase (MAPK) pathway [5].
The Cancer Genome Atlas (TCGA) has identified BRAF mutations in many different cancer types: 60% of melanomas, 60% of thyroid cancers, 15% of colorectal cancers, and 5–8% of non-small cell lung cancers [6]. Moreover, mutations in this gene are present in diffuse gliomas, cholangiocarcinoma, hairy cell leukemia, multiple myeloma, Langerhans cell histiocytosis and Erdheim–Chester disease [7].
Around 200 BRAF mutant alleles and 30 mutations of BRAF have been identified and characterized and V600E is the most common mutation [8]. BRAF mutations can be classified into three classes: class 1 and 2 are RAS-independent, while class 3 depends on RAS signaling [9].
Pembrolizumab and nivolumab for patients with high levels of microsatellite instability and deficient DNA mismatch repair (dMMR), and larotectinib for tropomyosin receptor kinases (TRK), have introduced the concept of tumor type agnostic therapy [10] where genomic alterations could be used to drive tumor therapy, regardless of tumor origin [11].
On the basis of this concept, in this report we describe two case studies in which treatment decisions have been driven by next generation sequencing (NGS). The first case study is that of a 59-year-old Caucasian man with BRAF V600E mutated intrahepatic cholangiocarcinoma (ICC). Intrahepatic cholangiocarcinoma is the second most common hepatic cancer and its incidence is increasing worldwide [4]. One of its targetable alterations is a v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation. While BRAF mutations are rare in pancreato-biliary cancers, they are reported with higher frequency, about 5% of all cases, in ICC [12]. The majority of mutations occur at the V600 position, with V600E observed in 5% of cholangiocarcinoma (CCA) [13].
The second case study is that of a 50-year-old, Caucasian woman, with BRAF G466A mutated Bellini duct carcinoma (BDC). BDC is a very rare and aggressive variant of kidney carcinoma, arising from the renal medulla, possibly from the distal collecting ducts of Bellini [14]. BDC is characterized by an aggressive clinical course and an extremely poor prognosis [15]. Less than one-third of patients survive more than 2 years after diagnosis, and in most reported cases metastatic disease is present ab initio. Radical nephrectomy is generally performed, followed by medical treatments such as immunotherapy, targeted therapies or chemotherapy [16]. Given the rarity of this cancer, it has been difficult to conduct large-scale clinical trials and a specific standard treatment has not yet been established.
These clinical cases may represent a proof of concept of how identifying and targeting potential molecular drivers, such as BRAF mutations, independently of tissue origin, could provide represent therapeutic opportunities, especially for rare cancers.
2. Case Presentation
2.1. Case 1
A 59-year-old Caucasian male patient, with metabolic syndrome and type 2 diabetes, was admitted to the emergency department in January 2017 with severe hip pain, nausea and increasing discomfort. Abdominal ultrasound and computerized axial tomography showed the presence of a 6 × 9 cm hepatic nodule in the VI segment. In February 2017 the patient underwent VI hepatic segment resection and cholecystectomy. Immunohistochemistry revealed moderately differentiated CCA, positive for CK7, CK19 and CA19, and negative for CK20. The patient was diagnosed with cT2aN0M0 disease. Indication to standard follow-up was given due to the absence of resection margins and lymph node involvement. However, in September 2017, after seven months of follow-up, positron emission tomography (PET) showed hyperfixation of the ischio-pubic branch and sacro-iliac articulation. The subsequent ischio-pubic biopsy revealed cholangiocarcinoma metastasis. At this point, first line chemotherapy with cisplatin (25 mg/m2) and gemcitabine (1000 mg/m2) on day 1 and 8 every 3 weeks was administered for 6 cycles. Furthermore, palliative radiotherapy was performed on the bone metastasis (20 Gy in fraction 5). After 6 cycles of chemotherapy, CT scans showed hepatic, lung, lymphonodal and bone disease progression. In June 2018, after multidisciplinary discussion, the patient started a second line chemotherapy with oxaliplatin (130 mg/m2) on day 1 and capecitabine (1000 mg/m2) orally BID for 14 days every 3 weeks, without clinical and radiological response.
In light of tumor resistance to second line chemotherapy, primary tumor next generation sequencing was performed in January 2019, which showed the presence of a BRAF V600E mutation. Given this result, it was decided to start off-label use of vemurafenib (960 mg/day) and cobimetinib (60 mg/day). During the course of this therapy, he remained almost completely asymptomatic, with the exception of some episodes of grade 2 nausea and self-limiting skin rash, which occurred during the first month. Biochemical evaluations showed an increase in alkaline phosphatase and blood creatine phosphokinase during the first and second month, respectively. Six months after beginning targeted therapy, restaging CT scans reported a treatment response, with an additional reduction of pulmonary nodules and hepatic lesions. Furthermore, the bone lesions appeared sclerotic due to treatment response. His last CT scan was performed in September 2020 and confirmed stable disease (Figure 1). To date, the patient is still on treatment.
In addition, EORTC QLQ-C30 (a standardized quality of life questionnaire) was conducted both at the beginning of treatment and after the latest radiological evaluation, revealing a progressive improvement in physical functioning (essential abilities for maintaining independence) and role functioning (abilities for work/leisure). Moreover, the patient has gradually reduced opioid intake until complete suspension.
2.2. Case 2
In January 2015, a 50-year-old, Caucasian woman, without comorbidities, was admitted to our hospital with a painless gross hematuria lasting 3 months. Physical examination revealed a percussion pain over the left kidney region and no extrarenal manifestations were found at clinical and laboratory examinations. A kidney tumor was suspected on the basis of the urinary system ultrasonography and the finding was subsequently confirmed with a total body CT scan. The imaging revealed a 3 × 3.5 cm heterogeneous enhancing mass, in the middle pole of the left kidney, which was further compounded with multiple metastases in the retroperitoneal lymph nodes, ovaries and a 12 mm temporal lobe brain lesion without perilesional edema. The patient subsequently underwent laparoscopic nephroureterectomy.
The final pathological report showed Bellini duct carcinoma (BDC) of the left kidney, Fuhrman Nuclear Grade IV. The histological diagnosis of BDC was confirmed by positive immunohistochemical staining with UEA-1 and EMA, and negative staining with Leu-M1 [17]. According to the American Joint Committee on Cancer (AJCC) 2015 classification and TNM classification, the patient was diagnosed with a high-grade, stage 4 disease.
After multidisciplinary discussion, in February 2015, the patient started first line chemotherapy with bevacizumab (15 mg/kg) and gemcitabine (1250 mg/m2) on days 1 and 8 and platinum salt (cisplatin 80 mg/m2 or carboplatin AUC 5 mg/ml/min) every 3 weeks. After 3 cycles, she obtained a clinical response and a CT scan showed partial radiological response. At this stage, one of the ovarian metastasis was resected in order to create a patient-derived xenograft (PDX). At the end of the 5th cycle, she developed febrile neutropenia (neu < 500/mm3). In light of the hematological toxicity, the chemotherapy was stopped while maintaining bevacizumab every 3 weeks. Maintenance therapy was well tolerated. Furthermore, stereotaxic radiotherapy was performed on the brain metastasis (24 Gray in 2 fractions).
After 6 cycles of maintenance bevacizumab (December 2015), retroperitoneal lymph node disease progressed. Using the PDX mouse-derived model, we were able to perform a mutational analysis.
Genomic sequencing of the ovarian metastasis revealed a BRAF G466A mutation. Hence, a therapeutic combination of trametinib and dabrafenib was started. After one month of therapy, the patient developed pyrexia and rash treated with common medications; however, the 18F-FDG-PET/CT performed at the beginning of treatment and repeated after 4 weeks showed decreased FDG avidity in the ovary and lymph node metastases (Figure 2).
From January 2016 to December 2016 the patient showed stable disease. However, in January 2017, she was admitted to the emergency department complaining of headaches, nausea and dizziness; her performance status worsened to 3, requiring the patient to be hospitalized. Brain CT scans revealed multiple metastases in the frontal, parietal and temporal lobe bilaterally, further confirmed by MRI. After one week, the patient passed away due to widespread brain metastasis. The disease was under control for 11 months after the first relapse.
3. Discussion
In 2011, the Food and Drug Administration approved the BRAF inhibitor vemurafenib for the treatment of BRAF V600E mutant metastatic melanoma [18]. Dabrafenib, another BRAF inhibitor, obtained FDA approval in 2013 [19]. In the coBRIM trial, Larkin J et al. demonstrated that the combination of vemurafenib with the MEK inhibitor cobimetinib resulted in significant progression-free survival (PFS) improvement among patients with BRAF V600E mutated metastatic melanoma in comparison to the combination of vemurafenib with placebo [20]. More recent studies showed that combining BRAF and MEK inhibitors determines a PFS improvement from a median of 7 months to 12 months in this setting [21]. Furthermore, the combination of MEK and BRAF inhibitors can decrease the onset of resistance to treatment and side effects that arise during BRAF inhibitor monotherapy [22]. This combination reduces the incidence of skin toxicity, including cutaneous squamous carcinoma associated with BRAF inhibition [23]. In mutated cells, B-raf protein is found in its hyperactive form. Combined BRAF inhibitors block the Ras-Raf-MEK-MAPK kinase pathway, but, as it happens with monotherapy, pharmacological resistance may develop after 6–7 months of treatment. To overcome this resistance, BRAF inhibitors are used in combination with MEK inhibitors which mediate the blockade of MAPK kinase (MEK), downstream of BRAF in the MAPK pathway [24]. Beside melanoma, thyroid cancers [25] and colon cancers [26], the prevalence of a BRAF V600E mutation in other cancers is less than 5% [27]. The relatively low frequency of this mutation accounts for the lack of randomized controlled studies looking at the use of specific anti-BRAF targeted therapies in other cancers. This difficulty is even true in the case of very rare tumors such as CCA and BDC, so that tumor-specific studies are almost impossible to run. On the other hand, the lack of therapeutic options for these rare diseases provides a strong rationale for targeting putative driver mutations.
To address such paradoxes, basket trials have come to the rescue, putting together tumors with different histology, on the basis of their molecular landscapes and, more specifically, the presence of a BRAF V600E mutation [28]. Whilst this approach still has limitations, such as the small number of patients enrolled per tumor type, and therefore there is low statistical power in the studies, some important indications can be drawn from them. Hyman et al. report results from a basket trial including a total of 122 patients with BRAF V600E mutation-positive cancers [29]. The primary end point of the study was the response rate; secondary end points were progression-free survival and overall survival. As the response varied across tumor types, the authors concluded that BRAF V600E mutation is certainly targetable in many, but not all, cancers, and that perhaps the tumor site in which they develop are important in determining the degree of response to a specific targeted therapy. The study had 6 tumor cohorts plus an “all other cancers” cohort. Clinical activity, including some complete responses, was observed in NSCLC, Langerhans cell histiocytosis, anaplastic thyroid cancer, ovarian cancer and cholangiocarcinoma. Colon cancer patients did not show any response to vemurafenib single-agent therapy and even when the anti-BRAF therapy was combined with cetuximab the results were not encouraging. These patients were however heavily pretreated, having had 1 to 6 previous lines of therapy [29]. The contribution of mutated BRAF seems to change amongst tumor types, as suggested by the very heterogeneous results in terms of clinical benefit of BRAF inhibition in different cancers. For instance, this mutation alone may not sufficient to drive tumor progression in certain tumor types, such as colon cancer [30].
Thus, the question of whether all BRAF-mutated cancers are amenable to specific targeted therapy is still open. Perhaps, extremely rare tumors and orphan cancers, where proven effective treatment strategies are lacking, could benefit by even modest therapeutic activity. Cholangiocarcinoma is one of the most aggressive biliary tract malignancies [31]. After first-line therapy, no standard second-line treatment has been established yet and the outcome remains rather poor, with a 5-year overall survival rate of around 2% due to metastatic disease [32]. Data from the literature show that nearly 35% of CCA harbor potentially targetable genomic alterations and the use of molecular profiling has led to the discovery of potential disease drivers [33]. Lowery MA et al. showed that IDH1 (25%), TP53 (24%), ARID1A (21%), BAP1 (15%), KRAS (13%), PBRM1 (12%), SMAD (9%), ATM (8%), BRAF (<5%) and MSI-H (0.5%) are the most commonly mutated genes in CCA [13]. Biliary tract cancer reveals molecular heterogeneity and there is a crucial need to identify a subset of patients who can benefit from targeted therapy to be used after progression on first-line treatment gemcitabine plus cisplatin [34]. The ClarIDHy study showed that ivosidenub significantly improved PFS, with a trend towards favorable overall survival, in comparison to placebo in patients with advanced cholangiocarcinoma carrying an IDH1 mutation [35]. At ASCO GI 2019, Park et al. presented encouraging preliminary results on the efficacy of erdafitinib in FGFR-mutated CCA patients as a second-line therapy (NCT 02699606). Andersen et al. reported that BRAF V600E occurs with the highest frequency in ICC (1.5%) and is associated with poor prognosis [36]. Focusing on biliary tract cancer, preliminary data from the ROAR basket trial demonstrated promising activity of dabrafenib plus trametinib with a favorable safety profile in patients with BRAF V600E (ROAR trial; NCT 02034110).
Based on all these results, we decided to administer a combination of MEK and BRAF inhibitors in a patient with BRAF mutant, chemotherapy-refractory ICC and obtained results in line with the few cases reported in literature. Lavingia et al. described two cases reaching 9 and 12 months PFS when treated with dabrafenib and trametinib [37]. Bunyatov et al. showed the longest remission with the same combination: a full response after 7 months of treatment with complete remission lasting 28 months [38]. In the second case, the PDX model predicted clinical response to dabrafenib and trametinib. BDC is a rare subtype of renal cell carcinoma with an extremely poor prognosis. Given the rarity of BDC and therefore the scarcity of specific clinical trials, the best treatment for this tumor remains uncertain. The only combination of cytotoxic agents which shows effectiveness is gemcitabine plus platinum [39]. Oudard et al. showed a 26% objective response in BDC with the gemcitabine plus platinum salt regimen used as a first-line treatment [40]. Furthermore, recent data also suggest a role for anti-angiogenic therapy in this setting. Péchuchet et al. demonstrated that addition of bevacizumab to platinum-based chemotherapy in previously untreated BDC patients resulted in longer PFS and OS, with a manageable safety profile [41]. In his BDC case report, El Mehdi Tazi et al. demonstrated a therapeutic response to sunitinib [42] and Ansari J et al. showed similar results with sorafenib [43]. Unfortunately, clinical trials failed to show activity of any targeted drugs [44]. Sharing common morphological and biological characteristics with urothelial carcinomas, to date, chemotherapy remains the standard treatment for patients with BDC. Nevertheless, after progression with first-line chemotherapy, the second-line approach still presents a challenge, and patient outcome remains poor. For this reason and on the basis of the genomic sequencing results, with the presence of a BRAF G466A mutation, we decided to use the combination of anti-BRAF and anti-MEK treatment. G466A belongs to Class 3 BRAF mutations depending on RAS signaling: thus, blocking RAS signaling would appear to be a potential therapeutic strategy for class 3 BRAF-mutant tumors, but to date there are no specific inhibitors available [45].
4. Conclusions
In the last few years, there have been increasing efforts to understand the molecular biology of several rare tumors with limited treatment options. Genome analysis could, in these cases, help find specific genomic alterations which can be targeted. Precision medicine allows a personalized approach based on biomarker individualization [46].
The approval of the first-in-class tumor agnostic therapies shows that identification of biomarkers independent from tumor origin could offer new treatment options with drugs already on the market [47].
In the literature, there is strong evidence that different tumors with BRAF mutations are good targets for BRAF/MEK pathway inhibitors and our work adds to this evidence.
This report highlights the importance of molecular profiling for the management of solid tumors, and more specifically, orphan tumors. In the era of precision medicine, patients with otherwise very grim expectations can benefit from such approaches while we wait for more prospective studies to provide evidence.
Acknowledgments
The authors express sincerest gratitude to the two patients and their families, the medical staff of doctors, nurses, scientists, health and administrative personnel for the strenuous work in such a delicate moment for healthcare.
Author Contributions
Conceptualization, D.G.; investigation, O.B., C.S., M.M., and D.G.; resources, M.R.C., G.F., N.Z., V.C. and A.M.; data curation, O.B. and M.S.; writing—original draft preparation, O.B. an M.S.; writing—review and editing, S.P.C. and G.R.; supervision, D.G.; project administration, D.G.; funding acquisition, D.G. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by MEDnoTE srl (Spin-off—University of Trieste).
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of ATS Val Padana (protocol code 42998 approved on 21 december 2018).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Data is available from the authors upon request.
Conflicts of Interest
DG reports personal fees for consulting, advisory role and speakers’ bureau from Novartis, Pfizer, Lilly; fees for travel and accommodations from Novartis, Pfizer, Lilly. Other authors have no potential conflicts of interest to disclose.
Ethical Approval and Consent to Participate
All patients signed the informed consent related to the Mozart protocol. We obtained the Local Ethics Committee Val Padana approval related to the Mozart protocol (code 42998) on the 21 December 2018. The Mozart protocol is a program to understand the molecular aberrations related resistance/responsiveness to novel drugs in metastatic solid tumors.
Figure 1 (a) CT scan, March 2019; (b) CT scan, September 2020.
Figure 2 FDG-PET after 4 weeks of treatment with dabrafenib and trametinib showed decreased FDG avidity. (a) FDG-PET performed in January; (b) FDG-PET performed in February 2016.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BEVACIZUMAB, CARBOPLATIN, CISPLATIN, DABRAFENIB, GEMCITABINE, TRAMETINIB | DrugsGivenReaction | CC BY | 33669326 | 19,926,457 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature.
BACKGROUND
Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy. The disease remained under control for 11 months after the first relapse.
CONCLUSIONS
In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors.
CONCLUSIONS
Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with.
1. Introduction
Over the past decade, tumor molecular profiling has been widely applied, leading to an individualized approach for patients termed “personalized” or “precision medicine”. This new approach has replaced the standard chemotherapy treatment based on the tumor’s origin, histology and nodal invasion (TNM) [1]. The aim of precision medicine is to define treatment based upon genomic drivers of tumorigenesis, thus identifying the best therapy for patients [2]. Moreover, precision oncology assesses tumor response to a specific treatment and finds drug resistance when it occurs [3].
The BRAF mutant is an oncogenic driver, since BRAF inactivation slows down systemic tumor growth and induces cancer cell toxicity [4]. BRAF is a member of the Raf kinase family and plays a critical role in cellular growth, proliferation and differentiation through the MAP-kinase (MAPK) pathway [5].
The Cancer Genome Atlas (TCGA) has identified BRAF mutations in many different cancer types: 60% of melanomas, 60% of thyroid cancers, 15% of colorectal cancers, and 5–8% of non-small cell lung cancers [6]. Moreover, mutations in this gene are present in diffuse gliomas, cholangiocarcinoma, hairy cell leukemia, multiple myeloma, Langerhans cell histiocytosis and Erdheim–Chester disease [7].
Around 200 BRAF mutant alleles and 30 mutations of BRAF have been identified and characterized and V600E is the most common mutation [8]. BRAF mutations can be classified into three classes: class 1 and 2 are RAS-independent, while class 3 depends on RAS signaling [9].
Pembrolizumab and nivolumab for patients with high levels of microsatellite instability and deficient DNA mismatch repair (dMMR), and larotectinib for tropomyosin receptor kinases (TRK), have introduced the concept of tumor type agnostic therapy [10] where genomic alterations could be used to drive tumor therapy, regardless of tumor origin [11].
On the basis of this concept, in this report we describe two case studies in which treatment decisions have been driven by next generation sequencing (NGS). The first case study is that of a 59-year-old Caucasian man with BRAF V600E mutated intrahepatic cholangiocarcinoma (ICC). Intrahepatic cholangiocarcinoma is the second most common hepatic cancer and its incidence is increasing worldwide [4]. One of its targetable alterations is a v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation. While BRAF mutations are rare in pancreato-biliary cancers, they are reported with higher frequency, about 5% of all cases, in ICC [12]. The majority of mutations occur at the V600 position, with V600E observed in 5% of cholangiocarcinoma (CCA) [13].
The second case study is that of a 50-year-old, Caucasian woman, with BRAF G466A mutated Bellini duct carcinoma (BDC). BDC is a very rare and aggressive variant of kidney carcinoma, arising from the renal medulla, possibly from the distal collecting ducts of Bellini [14]. BDC is characterized by an aggressive clinical course and an extremely poor prognosis [15]. Less than one-third of patients survive more than 2 years after diagnosis, and in most reported cases metastatic disease is present ab initio. Radical nephrectomy is generally performed, followed by medical treatments such as immunotherapy, targeted therapies or chemotherapy [16]. Given the rarity of this cancer, it has been difficult to conduct large-scale clinical trials and a specific standard treatment has not yet been established.
These clinical cases may represent a proof of concept of how identifying and targeting potential molecular drivers, such as BRAF mutations, independently of tissue origin, could provide represent therapeutic opportunities, especially for rare cancers.
2. Case Presentation
2.1. Case 1
A 59-year-old Caucasian male patient, with metabolic syndrome and type 2 diabetes, was admitted to the emergency department in January 2017 with severe hip pain, nausea and increasing discomfort. Abdominal ultrasound and computerized axial tomography showed the presence of a 6 × 9 cm hepatic nodule in the VI segment. In February 2017 the patient underwent VI hepatic segment resection and cholecystectomy. Immunohistochemistry revealed moderately differentiated CCA, positive for CK7, CK19 and CA19, and negative for CK20. The patient was diagnosed with cT2aN0M0 disease. Indication to standard follow-up was given due to the absence of resection margins and lymph node involvement. However, in September 2017, after seven months of follow-up, positron emission tomography (PET) showed hyperfixation of the ischio-pubic branch and sacro-iliac articulation. The subsequent ischio-pubic biopsy revealed cholangiocarcinoma metastasis. At this point, first line chemotherapy with cisplatin (25 mg/m2) and gemcitabine (1000 mg/m2) on day 1 and 8 every 3 weeks was administered for 6 cycles. Furthermore, palliative radiotherapy was performed on the bone metastasis (20 Gy in fraction 5). After 6 cycles of chemotherapy, CT scans showed hepatic, lung, lymphonodal and bone disease progression. In June 2018, after multidisciplinary discussion, the patient started a second line chemotherapy with oxaliplatin (130 mg/m2) on day 1 and capecitabine (1000 mg/m2) orally BID for 14 days every 3 weeks, without clinical and radiological response.
In light of tumor resistance to second line chemotherapy, primary tumor next generation sequencing was performed in January 2019, which showed the presence of a BRAF V600E mutation. Given this result, it was decided to start off-label use of vemurafenib (960 mg/day) and cobimetinib (60 mg/day). During the course of this therapy, he remained almost completely asymptomatic, with the exception of some episodes of grade 2 nausea and self-limiting skin rash, which occurred during the first month. Biochemical evaluations showed an increase in alkaline phosphatase and blood creatine phosphokinase during the first and second month, respectively. Six months after beginning targeted therapy, restaging CT scans reported a treatment response, with an additional reduction of pulmonary nodules and hepatic lesions. Furthermore, the bone lesions appeared sclerotic due to treatment response. His last CT scan was performed in September 2020 and confirmed stable disease (Figure 1). To date, the patient is still on treatment.
In addition, EORTC QLQ-C30 (a standardized quality of life questionnaire) was conducted both at the beginning of treatment and after the latest radiological evaluation, revealing a progressive improvement in physical functioning (essential abilities for maintaining independence) and role functioning (abilities for work/leisure). Moreover, the patient has gradually reduced opioid intake until complete suspension.
2.2. Case 2
In January 2015, a 50-year-old, Caucasian woman, without comorbidities, was admitted to our hospital with a painless gross hematuria lasting 3 months. Physical examination revealed a percussion pain over the left kidney region and no extrarenal manifestations were found at clinical and laboratory examinations. A kidney tumor was suspected on the basis of the urinary system ultrasonography and the finding was subsequently confirmed with a total body CT scan. The imaging revealed a 3 × 3.5 cm heterogeneous enhancing mass, in the middle pole of the left kidney, which was further compounded with multiple metastases in the retroperitoneal lymph nodes, ovaries and a 12 mm temporal lobe brain lesion without perilesional edema. The patient subsequently underwent laparoscopic nephroureterectomy.
The final pathological report showed Bellini duct carcinoma (BDC) of the left kidney, Fuhrman Nuclear Grade IV. The histological diagnosis of BDC was confirmed by positive immunohistochemical staining with UEA-1 and EMA, and negative staining with Leu-M1 [17]. According to the American Joint Committee on Cancer (AJCC) 2015 classification and TNM classification, the patient was diagnosed with a high-grade, stage 4 disease.
After multidisciplinary discussion, in February 2015, the patient started first line chemotherapy with bevacizumab (15 mg/kg) and gemcitabine (1250 mg/m2) on days 1 and 8 and platinum salt (cisplatin 80 mg/m2 or carboplatin AUC 5 mg/ml/min) every 3 weeks. After 3 cycles, she obtained a clinical response and a CT scan showed partial radiological response. At this stage, one of the ovarian metastasis was resected in order to create a patient-derived xenograft (PDX). At the end of the 5th cycle, she developed febrile neutropenia (neu < 500/mm3). In light of the hematological toxicity, the chemotherapy was stopped while maintaining bevacizumab every 3 weeks. Maintenance therapy was well tolerated. Furthermore, stereotaxic radiotherapy was performed on the brain metastasis (24 Gray in 2 fractions).
After 6 cycles of maintenance bevacizumab (December 2015), retroperitoneal lymph node disease progressed. Using the PDX mouse-derived model, we were able to perform a mutational analysis.
Genomic sequencing of the ovarian metastasis revealed a BRAF G466A mutation. Hence, a therapeutic combination of trametinib and dabrafenib was started. After one month of therapy, the patient developed pyrexia and rash treated with common medications; however, the 18F-FDG-PET/CT performed at the beginning of treatment and repeated after 4 weeks showed decreased FDG avidity in the ovary and lymph node metastases (Figure 2).
From January 2016 to December 2016 the patient showed stable disease. However, in January 2017, she was admitted to the emergency department complaining of headaches, nausea and dizziness; her performance status worsened to 3, requiring the patient to be hospitalized. Brain CT scans revealed multiple metastases in the frontal, parietal and temporal lobe bilaterally, further confirmed by MRI. After one week, the patient passed away due to widespread brain metastasis. The disease was under control for 11 months after the first relapse.
3. Discussion
In 2011, the Food and Drug Administration approved the BRAF inhibitor vemurafenib for the treatment of BRAF V600E mutant metastatic melanoma [18]. Dabrafenib, another BRAF inhibitor, obtained FDA approval in 2013 [19]. In the coBRIM trial, Larkin J et al. demonstrated that the combination of vemurafenib with the MEK inhibitor cobimetinib resulted in significant progression-free survival (PFS) improvement among patients with BRAF V600E mutated metastatic melanoma in comparison to the combination of vemurafenib with placebo [20]. More recent studies showed that combining BRAF and MEK inhibitors determines a PFS improvement from a median of 7 months to 12 months in this setting [21]. Furthermore, the combination of MEK and BRAF inhibitors can decrease the onset of resistance to treatment and side effects that arise during BRAF inhibitor monotherapy [22]. This combination reduces the incidence of skin toxicity, including cutaneous squamous carcinoma associated with BRAF inhibition [23]. In mutated cells, B-raf protein is found in its hyperactive form. Combined BRAF inhibitors block the Ras-Raf-MEK-MAPK kinase pathway, but, as it happens with monotherapy, pharmacological resistance may develop after 6–7 months of treatment. To overcome this resistance, BRAF inhibitors are used in combination with MEK inhibitors which mediate the blockade of MAPK kinase (MEK), downstream of BRAF in the MAPK pathway [24]. Beside melanoma, thyroid cancers [25] and colon cancers [26], the prevalence of a BRAF V600E mutation in other cancers is less than 5% [27]. The relatively low frequency of this mutation accounts for the lack of randomized controlled studies looking at the use of specific anti-BRAF targeted therapies in other cancers. This difficulty is even true in the case of very rare tumors such as CCA and BDC, so that tumor-specific studies are almost impossible to run. On the other hand, the lack of therapeutic options for these rare diseases provides a strong rationale for targeting putative driver mutations.
To address such paradoxes, basket trials have come to the rescue, putting together tumors with different histology, on the basis of their molecular landscapes and, more specifically, the presence of a BRAF V600E mutation [28]. Whilst this approach still has limitations, such as the small number of patients enrolled per tumor type, and therefore there is low statistical power in the studies, some important indications can be drawn from them. Hyman et al. report results from a basket trial including a total of 122 patients with BRAF V600E mutation-positive cancers [29]. The primary end point of the study was the response rate; secondary end points were progression-free survival and overall survival. As the response varied across tumor types, the authors concluded that BRAF V600E mutation is certainly targetable in many, but not all, cancers, and that perhaps the tumor site in which they develop are important in determining the degree of response to a specific targeted therapy. The study had 6 tumor cohorts plus an “all other cancers” cohort. Clinical activity, including some complete responses, was observed in NSCLC, Langerhans cell histiocytosis, anaplastic thyroid cancer, ovarian cancer and cholangiocarcinoma. Colon cancer patients did not show any response to vemurafenib single-agent therapy and even when the anti-BRAF therapy was combined with cetuximab the results were not encouraging. These patients were however heavily pretreated, having had 1 to 6 previous lines of therapy [29]. The contribution of mutated BRAF seems to change amongst tumor types, as suggested by the very heterogeneous results in terms of clinical benefit of BRAF inhibition in different cancers. For instance, this mutation alone may not sufficient to drive tumor progression in certain tumor types, such as colon cancer [30].
Thus, the question of whether all BRAF-mutated cancers are amenable to specific targeted therapy is still open. Perhaps, extremely rare tumors and orphan cancers, where proven effective treatment strategies are lacking, could benefit by even modest therapeutic activity. Cholangiocarcinoma is one of the most aggressive biliary tract malignancies [31]. After first-line therapy, no standard second-line treatment has been established yet and the outcome remains rather poor, with a 5-year overall survival rate of around 2% due to metastatic disease [32]. Data from the literature show that nearly 35% of CCA harbor potentially targetable genomic alterations and the use of molecular profiling has led to the discovery of potential disease drivers [33]. Lowery MA et al. showed that IDH1 (25%), TP53 (24%), ARID1A (21%), BAP1 (15%), KRAS (13%), PBRM1 (12%), SMAD (9%), ATM (8%), BRAF (<5%) and MSI-H (0.5%) are the most commonly mutated genes in CCA [13]. Biliary tract cancer reveals molecular heterogeneity and there is a crucial need to identify a subset of patients who can benefit from targeted therapy to be used after progression on first-line treatment gemcitabine plus cisplatin [34]. The ClarIDHy study showed that ivosidenub significantly improved PFS, with a trend towards favorable overall survival, in comparison to placebo in patients with advanced cholangiocarcinoma carrying an IDH1 mutation [35]. At ASCO GI 2019, Park et al. presented encouraging preliminary results on the efficacy of erdafitinib in FGFR-mutated CCA patients as a second-line therapy (NCT 02699606). Andersen et al. reported that BRAF V600E occurs with the highest frequency in ICC (1.5%) and is associated with poor prognosis [36]. Focusing on biliary tract cancer, preliminary data from the ROAR basket trial demonstrated promising activity of dabrafenib plus trametinib with a favorable safety profile in patients with BRAF V600E (ROAR trial; NCT 02034110).
Based on all these results, we decided to administer a combination of MEK and BRAF inhibitors in a patient with BRAF mutant, chemotherapy-refractory ICC and obtained results in line with the few cases reported in literature. Lavingia et al. described two cases reaching 9 and 12 months PFS when treated with dabrafenib and trametinib [37]. Bunyatov et al. showed the longest remission with the same combination: a full response after 7 months of treatment with complete remission lasting 28 months [38]. In the second case, the PDX model predicted clinical response to dabrafenib and trametinib. BDC is a rare subtype of renal cell carcinoma with an extremely poor prognosis. Given the rarity of BDC and therefore the scarcity of specific clinical trials, the best treatment for this tumor remains uncertain. The only combination of cytotoxic agents which shows effectiveness is gemcitabine plus platinum [39]. Oudard et al. showed a 26% objective response in BDC with the gemcitabine plus platinum salt regimen used as a first-line treatment [40]. Furthermore, recent data also suggest a role for anti-angiogenic therapy in this setting. Péchuchet et al. demonstrated that addition of bevacizumab to platinum-based chemotherapy in previously untreated BDC patients resulted in longer PFS and OS, with a manageable safety profile [41]. In his BDC case report, El Mehdi Tazi et al. demonstrated a therapeutic response to sunitinib [42] and Ansari J et al. showed similar results with sorafenib [43]. Unfortunately, clinical trials failed to show activity of any targeted drugs [44]. Sharing common morphological and biological characteristics with urothelial carcinomas, to date, chemotherapy remains the standard treatment for patients with BDC. Nevertheless, after progression with first-line chemotherapy, the second-line approach still presents a challenge, and patient outcome remains poor. For this reason and on the basis of the genomic sequencing results, with the presence of a BRAF G466A mutation, we decided to use the combination of anti-BRAF and anti-MEK treatment. G466A belongs to Class 3 BRAF mutations depending on RAS signaling: thus, blocking RAS signaling would appear to be a potential therapeutic strategy for class 3 BRAF-mutant tumors, but to date there are no specific inhibitors available [45].
4. Conclusions
In the last few years, there have been increasing efforts to understand the molecular biology of several rare tumors with limited treatment options. Genome analysis could, in these cases, help find specific genomic alterations which can be targeted. Precision medicine allows a personalized approach based on biomarker individualization [46].
The approval of the first-in-class tumor agnostic therapies shows that identification of biomarkers independent from tumor origin could offer new treatment options with drugs already on the market [47].
In the literature, there is strong evidence that different tumors with BRAF mutations are good targets for BRAF/MEK pathway inhibitors and our work adds to this evidence.
This report highlights the importance of molecular profiling for the management of solid tumors, and more specifically, orphan tumors. In the era of precision medicine, patients with otherwise very grim expectations can benefit from such approaches while we wait for more prospective studies to provide evidence.
Acknowledgments
The authors express sincerest gratitude to the two patients and their families, the medical staff of doctors, nurses, scientists, health and administrative personnel for the strenuous work in such a delicate moment for healthcare.
Author Contributions
Conceptualization, D.G.; investigation, O.B., C.S., M.M., and D.G.; resources, M.R.C., G.F., N.Z., V.C. and A.M.; data curation, O.B. and M.S.; writing—original draft preparation, O.B. an M.S.; writing—review and editing, S.P.C. and G.R.; supervision, D.G.; project administration, D.G.; funding acquisition, D.G. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by MEDnoTE srl (Spin-off—University of Trieste).
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of ATS Val Padana (protocol code 42998 approved on 21 december 2018).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Data is available from the authors upon request.
Conflicts of Interest
DG reports personal fees for consulting, advisory role and speakers’ bureau from Novartis, Pfizer, Lilly; fees for travel and accommodations from Novartis, Pfizer, Lilly. Other authors have no potential conflicts of interest to disclose.
Ethical Approval and Consent to Participate
All patients signed the informed consent related to the Mozart protocol. We obtained the Local Ethics Committee Val Padana approval related to the Mozart protocol (code 42998) on the 21 December 2018. The Mozart protocol is a program to understand the molecular aberrations related resistance/responsiveness to novel drugs in metastatic solid tumors.
Figure 1 (a) CT scan, March 2019; (b) CT scan, September 2020.
Figure 2 FDG-PET after 4 weeks of treatment with dabrafenib and trametinib showed decreased FDG avidity. (a) FDG-PET performed in January; (b) FDG-PET performed in February 2016.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BEVACIZUMAB, CARBOPLATIN, CISPLATIN, GEMCITABINE | DrugsGivenReaction | CC BY | 33669326 | 19,897,610 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy non-responder'. | Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature.
BACKGROUND
Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy. The disease remained under control for 11 months after the first relapse.
CONCLUSIONS
In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors.
CONCLUSIONS
Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with.
1. Introduction
Over the past decade, tumor molecular profiling has been widely applied, leading to an individualized approach for patients termed “personalized” or “precision medicine”. This new approach has replaced the standard chemotherapy treatment based on the tumor’s origin, histology and nodal invasion (TNM) [1]. The aim of precision medicine is to define treatment based upon genomic drivers of tumorigenesis, thus identifying the best therapy for patients [2]. Moreover, precision oncology assesses tumor response to a specific treatment and finds drug resistance when it occurs [3].
The BRAF mutant is an oncogenic driver, since BRAF inactivation slows down systemic tumor growth and induces cancer cell toxicity [4]. BRAF is a member of the Raf kinase family and plays a critical role in cellular growth, proliferation and differentiation through the MAP-kinase (MAPK) pathway [5].
The Cancer Genome Atlas (TCGA) has identified BRAF mutations in many different cancer types: 60% of melanomas, 60% of thyroid cancers, 15% of colorectal cancers, and 5–8% of non-small cell lung cancers [6]. Moreover, mutations in this gene are present in diffuse gliomas, cholangiocarcinoma, hairy cell leukemia, multiple myeloma, Langerhans cell histiocytosis and Erdheim–Chester disease [7].
Around 200 BRAF mutant alleles and 30 mutations of BRAF have been identified and characterized and V600E is the most common mutation [8]. BRAF mutations can be classified into three classes: class 1 and 2 are RAS-independent, while class 3 depends on RAS signaling [9].
Pembrolizumab and nivolumab for patients with high levels of microsatellite instability and deficient DNA mismatch repair (dMMR), and larotectinib for tropomyosin receptor kinases (TRK), have introduced the concept of tumor type agnostic therapy [10] where genomic alterations could be used to drive tumor therapy, regardless of tumor origin [11].
On the basis of this concept, in this report we describe two case studies in which treatment decisions have been driven by next generation sequencing (NGS). The first case study is that of a 59-year-old Caucasian man with BRAF V600E mutated intrahepatic cholangiocarcinoma (ICC). Intrahepatic cholangiocarcinoma is the second most common hepatic cancer and its incidence is increasing worldwide [4]. One of its targetable alterations is a v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation. While BRAF mutations are rare in pancreato-biliary cancers, they are reported with higher frequency, about 5% of all cases, in ICC [12]. The majority of mutations occur at the V600 position, with V600E observed in 5% of cholangiocarcinoma (CCA) [13].
The second case study is that of a 50-year-old, Caucasian woman, with BRAF G466A mutated Bellini duct carcinoma (BDC). BDC is a very rare and aggressive variant of kidney carcinoma, arising from the renal medulla, possibly from the distal collecting ducts of Bellini [14]. BDC is characterized by an aggressive clinical course and an extremely poor prognosis [15]. Less than one-third of patients survive more than 2 years after diagnosis, and in most reported cases metastatic disease is present ab initio. Radical nephrectomy is generally performed, followed by medical treatments such as immunotherapy, targeted therapies or chemotherapy [16]. Given the rarity of this cancer, it has been difficult to conduct large-scale clinical trials and a specific standard treatment has not yet been established.
These clinical cases may represent a proof of concept of how identifying and targeting potential molecular drivers, such as BRAF mutations, independently of tissue origin, could provide represent therapeutic opportunities, especially for rare cancers.
2. Case Presentation
2.1. Case 1
A 59-year-old Caucasian male patient, with metabolic syndrome and type 2 diabetes, was admitted to the emergency department in January 2017 with severe hip pain, nausea and increasing discomfort. Abdominal ultrasound and computerized axial tomography showed the presence of a 6 × 9 cm hepatic nodule in the VI segment. In February 2017 the patient underwent VI hepatic segment resection and cholecystectomy. Immunohistochemistry revealed moderately differentiated CCA, positive for CK7, CK19 and CA19, and negative for CK20. The patient was diagnosed with cT2aN0M0 disease. Indication to standard follow-up was given due to the absence of resection margins and lymph node involvement. However, in September 2017, after seven months of follow-up, positron emission tomography (PET) showed hyperfixation of the ischio-pubic branch and sacro-iliac articulation. The subsequent ischio-pubic biopsy revealed cholangiocarcinoma metastasis. At this point, first line chemotherapy with cisplatin (25 mg/m2) and gemcitabine (1000 mg/m2) on day 1 and 8 every 3 weeks was administered for 6 cycles. Furthermore, palliative radiotherapy was performed on the bone metastasis (20 Gy in fraction 5). After 6 cycles of chemotherapy, CT scans showed hepatic, lung, lymphonodal and bone disease progression. In June 2018, after multidisciplinary discussion, the patient started a second line chemotherapy with oxaliplatin (130 mg/m2) on day 1 and capecitabine (1000 mg/m2) orally BID for 14 days every 3 weeks, without clinical and radiological response.
In light of tumor resistance to second line chemotherapy, primary tumor next generation sequencing was performed in January 2019, which showed the presence of a BRAF V600E mutation. Given this result, it was decided to start off-label use of vemurafenib (960 mg/day) and cobimetinib (60 mg/day). During the course of this therapy, he remained almost completely asymptomatic, with the exception of some episodes of grade 2 nausea and self-limiting skin rash, which occurred during the first month. Biochemical evaluations showed an increase in alkaline phosphatase and blood creatine phosphokinase during the first and second month, respectively. Six months after beginning targeted therapy, restaging CT scans reported a treatment response, with an additional reduction of pulmonary nodules and hepatic lesions. Furthermore, the bone lesions appeared sclerotic due to treatment response. His last CT scan was performed in September 2020 and confirmed stable disease (Figure 1). To date, the patient is still on treatment.
In addition, EORTC QLQ-C30 (a standardized quality of life questionnaire) was conducted both at the beginning of treatment and after the latest radiological evaluation, revealing a progressive improvement in physical functioning (essential abilities for maintaining independence) and role functioning (abilities for work/leisure). Moreover, the patient has gradually reduced opioid intake until complete suspension.
2.2. Case 2
In January 2015, a 50-year-old, Caucasian woman, without comorbidities, was admitted to our hospital with a painless gross hematuria lasting 3 months. Physical examination revealed a percussion pain over the left kidney region and no extrarenal manifestations were found at clinical and laboratory examinations. A kidney tumor was suspected on the basis of the urinary system ultrasonography and the finding was subsequently confirmed with a total body CT scan. The imaging revealed a 3 × 3.5 cm heterogeneous enhancing mass, in the middle pole of the left kidney, which was further compounded with multiple metastases in the retroperitoneal lymph nodes, ovaries and a 12 mm temporal lobe brain lesion without perilesional edema. The patient subsequently underwent laparoscopic nephroureterectomy.
The final pathological report showed Bellini duct carcinoma (BDC) of the left kidney, Fuhrman Nuclear Grade IV. The histological diagnosis of BDC was confirmed by positive immunohistochemical staining with UEA-1 and EMA, and negative staining with Leu-M1 [17]. According to the American Joint Committee on Cancer (AJCC) 2015 classification and TNM classification, the patient was diagnosed with a high-grade, stage 4 disease.
After multidisciplinary discussion, in February 2015, the patient started first line chemotherapy with bevacizumab (15 mg/kg) and gemcitabine (1250 mg/m2) on days 1 and 8 and platinum salt (cisplatin 80 mg/m2 or carboplatin AUC 5 mg/ml/min) every 3 weeks. After 3 cycles, she obtained a clinical response and a CT scan showed partial radiological response. At this stage, one of the ovarian metastasis was resected in order to create a patient-derived xenograft (PDX). At the end of the 5th cycle, she developed febrile neutropenia (neu < 500/mm3). In light of the hematological toxicity, the chemotherapy was stopped while maintaining bevacizumab every 3 weeks. Maintenance therapy was well tolerated. Furthermore, stereotaxic radiotherapy was performed on the brain metastasis (24 Gray in 2 fractions).
After 6 cycles of maintenance bevacizumab (December 2015), retroperitoneal lymph node disease progressed. Using the PDX mouse-derived model, we were able to perform a mutational analysis.
Genomic sequencing of the ovarian metastasis revealed a BRAF G466A mutation. Hence, a therapeutic combination of trametinib and dabrafenib was started. After one month of therapy, the patient developed pyrexia and rash treated with common medications; however, the 18F-FDG-PET/CT performed at the beginning of treatment and repeated after 4 weeks showed decreased FDG avidity in the ovary and lymph node metastases (Figure 2).
From January 2016 to December 2016 the patient showed stable disease. However, in January 2017, she was admitted to the emergency department complaining of headaches, nausea and dizziness; her performance status worsened to 3, requiring the patient to be hospitalized. Brain CT scans revealed multiple metastases in the frontal, parietal and temporal lobe bilaterally, further confirmed by MRI. After one week, the patient passed away due to widespread brain metastasis. The disease was under control for 11 months after the first relapse.
3. Discussion
In 2011, the Food and Drug Administration approved the BRAF inhibitor vemurafenib for the treatment of BRAF V600E mutant metastatic melanoma [18]. Dabrafenib, another BRAF inhibitor, obtained FDA approval in 2013 [19]. In the coBRIM trial, Larkin J et al. demonstrated that the combination of vemurafenib with the MEK inhibitor cobimetinib resulted in significant progression-free survival (PFS) improvement among patients with BRAF V600E mutated metastatic melanoma in comparison to the combination of vemurafenib with placebo [20]. More recent studies showed that combining BRAF and MEK inhibitors determines a PFS improvement from a median of 7 months to 12 months in this setting [21]. Furthermore, the combination of MEK and BRAF inhibitors can decrease the onset of resistance to treatment and side effects that arise during BRAF inhibitor monotherapy [22]. This combination reduces the incidence of skin toxicity, including cutaneous squamous carcinoma associated with BRAF inhibition [23]. In mutated cells, B-raf protein is found in its hyperactive form. Combined BRAF inhibitors block the Ras-Raf-MEK-MAPK kinase pathway, but, as it happens with monotherapy, pharmacological resistance may develop after 6–7 months of treatment. To overcome this resistance, BRAF inhibitors are used in combination with MEK inhibitors which mediate the blockade of MAPK kinase (MEK), downstream of BRAF in the MAPK pathway [24]. Beside melanoma, thyroid cancers [25] and colon cancers [26], the prevalence of a BRAF V600E mutation in other cancers is less than 5% [27]. The relatively low frequency of this mutation accounts for the lack of randomized controlled studies looking at the use of specific anti-BRAF targeted therapies in other cancers. This difficulty is even true in the case of very rare tumors such as CCA and BDC, so that tumor-specific studies are almost impossible to run. On the other hand, the lack of therapeutic options for these rare diseases provides a strong rationale for targeting putative driver mutations.
To address such paradoxes, basket trials have come to the rescue, putting together tumors with different histology, on the basis of their molecular landscapes and, more specifically, the presence of a BRAF V600E mutation [28]. Whilst this approach still has limitations, such as the small number of patients enrolled per tumor type, and therefore there is low statistical power in the studies, some important indications can be drawn from them. Hyman et al. report results from a basket trial including a total of 122 patients with BRAF V600E mutation-positive cancers [29]. The primary end point of the study was the response rate; secondary end points were progression-free survival and overall survival. As the response varied across tumor types, the authors concluded that BRAF V600E mutation is certainly targetable in many, but not all, cancers, and that perhaps the tumor site in which they develop are important in determining the degree of response to a specific targeted therapy. The study had 6 tumor cohorts plus an “all other cancers” cohort. Clinical activity, including some complete responses, was observed in NSCLC, Langerhans cell histiocytosis, anaplastic thyroid cancer, ovarian cancer and cholangiocarcinoma. Colon cancer patients did not show any response to vemurafenib single-agent therapy and even when the anti-BRAF therapy was combined with cetuximab the results were not encouraging. These patients were however heavily pretreated, having had 1 to 6 previous lines of therapy [29]. The contribution of mutated BRAF seems to change amongst tumor types, as suggested by the very heterogeneous results in terms of clinical benefit of BRAF inhibition in different cancers. For instance, this mutation alone may not sufficient to drive tumor progression in certain tumor types, such as colon cancer [30].
Thus, the question of whether all BRAF-mutated cancers are amenable to specific targeted therapy is still open. Perhaps, extremely rare tumors and orphan cancers, where proven effective treatment strategies are lacking, could benefit by even modest therapeutic activity. Cholangiocarcinoma is one of the most aggressive biliary tract malignancies [31]. After first-line therapy, no standard second-line treatment has been established yet and the outcome remains rather poor, with a 5-year overall survival rate of around 2% due to metastatic disease [32]. Data from the literature show that nearly 35% of CCA harbor potentially targetable genomic alterations and the use of molecular profiling has led to the discovery of potential disease drivers [33]. Lowery MA et al. showed that IDH1 (25%), TP53 (24%), ARID1A (21%), BAP1 (15%), KRAS (13%), PBRM1 (12%), SMAD (9%), ATM (8%), BRAF (<5%) and MSI-H (0.5%) are the most commonly mutated genes in CCA [13]. Biliary tract cancer reveals molecular heterogeneity and there is a crucial need to identify a subset of patients who can benefit from targeted therapy to be used after progression on first-line treatment gemcitabine plus cisplatin [34]. The ClarIDHy study showed that ivosidenub significantly improved PFS, with a trend towards favorable overall survival, in comparison to placebo in patients with advanced cholangiocarcinoma carrying an IDH1 mutation [35]. At ASCO GI 2019, Park et al. presented encouraging preliminary results on the efficacy of erdafitinib in FGFR-mutated CCA patients as a second-line therapy (NCT 02699606). Andersen et al. reported that BRAF V600E occurs with the highest frequency in ICC (1.5%) and is associated with poor prognosis [36]. Focusing on biliary tract cancer, preliminary data from the ROAR basket trial demonstrated promising activity of dabrafenib plus trametinib with a favorable safety profile in patients with BRAF V600E (ROAR trial; NCT 02034110).
Based on all these results, we decided to administer a combination of MEK and BRAF inhibitors in a patient with BRAF mutant, chemotherapy-refractory ICC and obtained results in line with the few cases reported in literature. Lavingia et al. described two cases reaching 9 and 12 months PFS when treated with dabrafenib and trametinib [37]. Bunyatov et al. showed the longest remission with the same combination: a full response after 7 months of treatment with complete remission lasting 28 months [38]. In the second case, the PDX model predicted clinical response to dabrafenib and trametinib. BDC is a rare subtype of renal cell carcinoma with an extremely poor prognosis. Given the rarity of BDC and therefore the scarcity of specific clinical trials, the best treatment for this tumor remains uncertain. The only combination of cytotoxic agents which shows effectiveness is gemcitabine plus platinum [39]. Oudard et al. showed a 26% objective response in BDC with the gemcitabine plus platinum salt regimen used as a first-line treatment [40]. Furthermore, recent data also suggest a role for anti-angiogenic therapy in this setting. Péchuchet et al. demonstrated that addition of bevacizumab to platinum-based chemotherapy in previously untreated BDC patients resulted in longer PFS and OS, with a manageable safety profile [41]. In his BDC case report, El Mehdi Tazi et al. demonstrated a therapeutic response to sunitinib [42] and Ansari J et al. showed similar results with sorafenib [43]. Unfortunately, clinical trials failed to show activity of any targeted drugs [44]. Sharing common morphological and biological characteristics with urothelial carcinomas, to date, chemotherapy remains the standard treatment for patients with BDC. Nevertheless, after progression with first-line chemotherapy, the second-line approach still presents a challenge, and patient outcome remains poor. For this reason and on the basis of the genomic sequencing results, with the presence of a BRAF G466A mutation, we decided to use the combination of anti-BRAF and anti-MEK treatment. G466A belongs to Class 3 BRAF mutations depending on RAS signaling: thus, blocking RAS signaling would appear to be a potential therapeutic strategy for class 3 BRAF-mutant tumors, but to date there are no specific inhibitors available [45].
4. Conclusions
In the last few years, there have been increasing efforts to understand the molecular biology of several rare tumors with limited treatment options. Genome analysis could, in these cases, help find specific genomic alterations which can be targeted. Precision medicine allows a personalized approach based on biomarker individualization [46].
The approval of the first-in-class tumor agnostic therapies shows that identification of biomarkers independent from tumor origin could offer new treatment options with drugs already on the market [47].
In the literature, there is strong evidence that different tumors with BRAF mutations are good targets for BRAF/MEK pathway inhibitors and our work adds to this evidence.
This report highlights the importance of molecular profiling for the management of solid tumors, and more specifically, orphan tumors. In the era of precision medicine, patients with otherwise very grim expectations can benefit from such approaches while we wait for more prospective studies to provide evidence.
Acknowledgments
The authors express sincerest gratitude to the two patients and their families, the medical staff of doctors, nurses, scientists, health and administrative personnel for the strenuous work in such a delicate moment for healthcare.
Author Contributions
Conceptualization, D.G.; investigation, O.B., C.S., M.M., and D.G.; resources, M.R.C., G.F., N.Z., V.C. and A.M.; data curation, O.B. and M.S.; writing—original draft preparation, O.B. an M.S.; writing—review and editing, S.P.C. and G.R.; supervision, D.G.; project administration, D.G.; funding acquisition, D.G. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by MEDnoTE srl (Spin-off—University of Trieste).
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of ATS Val Padana (protocol code 42998 approved on 21 december 2018).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Data is available from the authors upon request.
Conflicts of Interest
DG reports personal fees for consulting, advisory role and speakers’ bureau from Novartis, Pfizer, Lilly; fees for travel and accommodations from Novartis, Pfizer, Lilly. Other authors have no potential conflicts of interest to disclose.
Ethical Approval and Consent to Participate
All patients signed the informed consent related to the Mozart protocol. We obtained the Local Ethics Committee Val Padana approval related to the Mozart protocol (code 42998) on the 21 December 2018. The Mozart protocol is a program to understand the molecular aberrations related resistance/responsiveness to novel drugs in metastatic solid tumors.
Figure 1 (a) CT scan, March 2019; (b) CT scan, September 2020.
Figure 2 FDG-PET after 4 weeks of treatment with dabrafenib and trametinib showed decreased FDG avidity. (a) FDG-PET performed in January; (b) FDG-PET performed in February 2016.
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What was the administration route of drug 'CAPECITABINE'? | Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature.
BACKGROUND
Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy. The disease remained under control for 11 months after the first relapse.
CONCLUSIONS
In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors.
CONCLUSIONS
Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with.
1. Introduction
Over the past decade, tumor molecular profiling has been widely applied, leading to an individualized approach for patients termed “personalized” or “precision medicine”. This new approach has replaced the standard chemotherapy treatment based on the tumor’s origin, histology and nodal invasion (TNM) [1]. The aim of precision medicine is to define treatment based upon genomic drivers of tumorigenesis, thus identifying the best therapy for patients [2]. Moreover, precision oncology assesses tumor response to a specific treatment and finds drug resistance when it occurs [3].
The BRAF mutant is an oncogenic driver, since BRAF inactivation slows down systemic tumor growth and induces cancer cell toxicity [4]. BRAF is a member of the Raf kinase family and plays a critical role in cellular growth, proliferation and differentiation through the MAP-kinase (MAPK) pathway [5].
The Cancer Genome Atlas (TCGA) has identified BRAF mutations in many different cancer types: 60% of melanomas, 60% of thyroid cancers, 15% of colorectal cancers, and 5–8% of non-small cell lung cancers [6]. Moreover, mutations in this gene are present in diffuse gliomas, cholangiocarcinoma, hairy cell leukemia, multiple myeloma, Langerhans cell histiocytosis and Erdheim–Chester disease [7].
Around 200 BRAF mutant alleles and 30 mutations of BRAF have been identified and characterized and V600E is the most common mutation [8]. BRAF mutations can be classified into three classes: class 1 and 2 are RAS-independent, while class 3 depends on RAS signaling [9].
Pembrolizumab and nivolumab for patients with high levels of microsatellite instability and deficient DNA mismatch repair (dMMR), and larotectinib for tropomyosin receptor kinases (TRK), have introduced the concept of tumor type agnostic therapy [10] where genomic alterations could be used to drive tumor therapy, regardless of tumor origin [11].
On the basis of this concept, in this report we describe two case studies in which treatment decisions have been driven by next generation sequencing (NGS). The first case study is that of a 59-year-old Caucasian man with BRAF V600E mutated intrahepatic cholangiocarcinoma (ICC). Intrahepatic cholangiocarcinoma is the second most common hepatic cancer and its incidence is increasing worldwide [4]. One of its targetable alterations is a v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation. While BRAF mutations are rare in pancreato-biliary cancers, they are reported with higher frequency, about 5% of all cases, in ICC [12]. The majority of mutations occur at the V600 position, with V600E observed in 5% of cholangiocarcinoma (CCA) [13].
The second case study is that of a 50-year-old, Caucasian woman, with BRAF G466A mutated Bellini duct carcinoma (BDC). BDC is a very rare and aggressive variant of kidney carcinoma, arising from the renal medulla, possibly from the distal collecting ducts of Bellini [14]. BDC is characterized by an aggressive clinical course and an extremely poor prognosis [15]. Less than one-third of patients survive more than 2 years after diagnosis, and in most reported cases metastatic disease is present ab initio. Radical nephrectomy is generally performed, followed by medical treatments such as immunotherapy, targeted therapies or chemotherapy [16]. Given the rarity of this cancer, it has been difficult to conduct large-scale clinical trials and a specific standard treatment has not yet been established.
These clinical cases may represent a proof of concept of how identifying and targeting potential molecular drivers, such as BRAF mutations, independently of tissue origin, could provide represent therapeutic opportunities, especially for rare cancers.
2. Case Presentation
2.1. Case 1
A 59-year-old Caucasian male patient, with metabolic syndrome and type 2 diabetes, was admitted to the emergency department in January 2017 with severe hip pain, nausea and increasing discomfort. Abdominal ultrasound and computerized axial tomography showed the presence of a 6 × 9 cm hepatic nodule in the VI segment. In February 2017 the patient underwent VI hepatic segment resection and cholecystectomy. Immunohistochemistry revealed moderately differentiated CCA, positive for CK7, CK19 and CA19, and negative for CK20. The patient was diagnosed with cT2aN0M0 disease. Indication to standard follow-up was given due to the absence of resection margins and lymph node involvement. However, in September 2017, after seven months of follow-up, positron emission tomography (PET) showed hyperfixation of the ischio-pubic branch and sacro-iliac articulation. The subsequent ischio-pubic biopsy revealed cholangiocarcinoma metastasis. At this point, first line chemotherapy with cisplatin (25 mg/m2) and gemcitabine (1000 mg/m2) on day 1 and 8 every 3 weeks was administered for 6 cycles. Furthermore, palliative radiotherapy was performed on the bone metastasis (20 Gy in fraction 5). After 6 cycles of chemotherapy, CT scans showed hepatic, lung, lymphonodal and bone disease progression. In June 2018, after multidisciplinary discussion, the patient started a second line chemotherapy with oxaliplatin (130 mg/m2) on day 1 and capecitabine (1000 mg/m2) orally BID for 14 days every 3 weeks, without clinical and radiological response.
In light of tumor resistance to second line chemotherapy, primary tumor next generation sequencing was performed in January 2019, which showed the presence of a BRAF V600E mutation. Given this result, it was decided to start off-label use of vemurafenib (960 mg/day) and cobimetinib (60 mg/day). During the course of this therapy, he remained almost completely asymptomatic, with the exception of some episodes of grade 2 nausea and self-limiting skin rash, which occurred during the first month. Biochemical evaluations showed an increase in alkaline phosphatase and blood creatine phosphokinase during the first and second month, respectively. Six months after beginning targeted therapy, restaging CT scans reported a treatment response, with an additional reduction of pulmonary nodules and hepatic lesions. Furthermore, the bone lesions appeared sclerotic due to treatment response. His last CT scan was performed in September 2020 and confirmed stable disease (Figure 1). To date, the patient is still on treatment.
In addition, EORTC QLQ-C30 (a standardized quality of life questionnaire) was conducted both at the beginning of treatment and after the latest radiological evaluation, revealing a progressive improvement in physical functioning (essential abilities for maintaining independence) and role functioning (abilities for work/leisure). Moreover, the patient has gradually reduced opioid intake until complete suspension.
2.2. Case 2
In January 2015, a 50-year-old, Caucasian woman, without comorbidities, was admitted to our hospital with a painless gross hematuria lasting 3 months. Physical examination revealed a percussion pain over the left kidney region and no extrarenal manifestations were found at clinical and laboratory examinations. A kidney tumor was suspected on the basis of the urinary system ultrasonography and the finding was subsequently confirmed with a total body CT scan. The imaging revealed a 3 × 3.5 cm heterogeneous enhancing mass, in the middle pole of the left kidney, which was further compounded with multiple metastases in the retroperitoneal lymph nodes, ovaries and a 12 mm temporal lobe brain lesion without perilesional edema. The patient subsequently underwent laparoscopic nephroureterectomy.
The final pathological report showed Bellini duct carcinoma (BDC) of the left kidney, Fuhrman Nuclear Grade IV. The histological diagnosis of BDC was confirmed by positive immunohistochemical staining with UEA-1 and EMA, and negative staining with Leu-M1 [17]. According to the American Joint Committee on Cancer (AJCC) 2015 classification and TNM classification, the patient was diagnosed with a high-grade, stage 4 disease.
After multidisciplinary discussion, in February 2015, the patient started first line chemotherapy with bevacizumab (15 mg/kg) and gemcitabine (1250 mg/m2) on days 1 and 8 and platinum salt (cisplatin 80 mg/m2 or carboplatin AUC 5 mg/ml/min) every 3 weeks. After 3 cycles, she obtained a clinical response and a CT scan showed partial radiological response. At this stage, one of the ovarian metastasis was resected in order to create a patient-derived xenograft (PDX). At the end of the 5th cycle, she developed febrile neutropenia (neu < 500/mm3). In light of the hematological toxicity, the chemotherapy was stopped while maintaining bevacizumab every 3 weeks. Maintenance therapy was well tolerated. Furthermore, stereotaxic radiotherapy was performed on the brain metastasis (24 Gray in 2 fractions).
After 6 cycles of maintenance bevacizumab (December 2015), retroperitoneal lymph node disease progressed. Using the PDX mouse-derived model, we were able to perform a mutational analysis.
Genomic sequencing of the ovarian metastasis revealed a BRAF G466A mutation. Hence, a therapeutic combination of trametinib and dabrafenib was started. After one month of therapy, the patient developed pyrexia and rash treated with common medications; however, the 18F-FDG-PET/CT performed at the beginning of treatment and repeated after 4 weeks showed decreased FDG avidity in the ovary and lymph node metastases (Figure 2).
From January 2016 to December 2016 the patient showed stable disease. However, in January 2017, she was admitted to the emergency department complaining of headaches, nausea and dizziness; her performance status worsened to 3, requiring the patient to be hospitalized. Brain CT scans revealed multiple metastases in the frontal, parietal and temporal lobe bilaterally, further confirmed by MRI. After one week, the patient passed away due to widespread brain metastasis. The disease was under control for 11 months after the first relapse.
3. Discussion
In 2011, the Food and Drug Administration approved the BRAF inhibitor vemurafenib for the treatment of BRAF V600E mutant metastatic melanoma [18]. Dabrafenib, another BRAF inhibitor, obtained FDA approval in 2013 [19]. In the coBRIM trial, Larkin J et al. demonstrated that the combination of vemurafenib with the MEK inhibitor cobimetinib resulted in significant progression-free survival (PFS) improvement among patients with BRAF V600E mutated metastatic melanoma in comparison to the combination of vemurafenib with placebo [20]. More recent studies showed that combining BRAF and MEK inhibitors determines a PFS improvement from a median of 7 months to 12 months in this setting [21]. Furthermore, the combination of MEK and BRAF inhibitors can decrease the onset of resistance to treatment and side effects that arise during BRAF inhibitor monotherapy [22]. This combination reduces the incidence of skin toxicity, including cutaneous squamous carcinoma associated with BRAF inhibition [23]. In mutated cells, B-raf protein is found in its hyperactive form. Combined BRAF inhibitors block the Ras-Raf-MEK-MAPK kinase pathway, but, as it happens with monotherapy, pharmacological resistance may develop after 6–7 months of treatment. To overcome this resistance, BRAF inhibitors are used in combination with MEK inhibitors which mediate the blockade of MAPK kinase (MEK), downstream of BRAF in the MAPK pathway [24]. Beside melanoma, thyroid cancers [25] and colon cancers [26], the prevalence of a BRAF V600E mutation in other cancers is less than 5% [27]. The relatively low frequency of this mutation accounts for the lack of randomized controlled studies looking at the use of specific anti-BRAF targeted therapies in other cancers. This difficulty is even true in the case of very rare tumors such as CCA and BDC, so that tumor-specific studies are almost impossible to run. On the other hand, the lack of therapeutic options for these rare diseases provides a strong rationale for targeting putative driver mutations.
To address such paradoxes, basket trials have come to the rescue, putting together tumors with different histology, on the basis of their molecular landscapes and, more specifically, the presence of a BRAF V600E mutation [28]. Whilst this approach still has limitations, such as the small number of patients enrolled per tumor type, and therefore there is low statistical power in the studies, some important indications can be drawn from them. Hyman et al. report results from a basket trial including a total of 122 patients with BRAF V600E mutation-positive cancers [29]. The primary end point of the study was the response rate; secondary end points were progression-free survival and overall survival. As the response varied across tumor types, the authors concluded that BRAF V600E mutation is certainly targetable in many, but not all, cancers, and that perhaps the tumor site in which they develop are important in determining the degree of response to a specific targeted therapy. The study had 6 tumor cohorts plus an “all other cancers” cohort. Clinical activity, including some complete responses, was observed in NSCLC, Langerhans cell histiocytosis, anaplastic thyroid cancer, ovarian cancer and cholangiocarcinoma. Colon cancer patients did not show any response to vemurafenib single-agent therapy and even when the anti-BRAF therapy was combined with cetuximab the results were not encouraging. These patients were however heavily pretreated, having had 1 to 6 previous lines of therapy [29]. The contribution of mutated BRAF seems to change amongst tumor types, as suggested by the very heterogeneous results in terms of clinical benefit of BRAF inhibition in different cancers. For instance, this mutation alone may not sufficient to drive tumor progression in certain tumor types, such as colon cancer [30].
Thus, the question of whether all BRAF-mutated cancers are amenable to specific targeted therapy is still open. Perhaps, extremely rare tumors and orphan cancers, where proven effective treatment strategies are lacking, could benefit by even modest therapeutic activity. Cholangiocarcinoma is one of the most aggressive biliary tract malignancies [31]. After first-line therapy, no standard second-line treatment has been established yet and the outcome remains rather poor, with a 5-year overall survival rate of around 2% due to metastatic disease [32]. Data from the literature show that nearly 35% of CCA harbor potentially targetable genomic alterations and the use of molecular profiling has led to the discovery of potential disease drivers [33]. Lowery MA et al. showed that IDH1 (25%), TP53 (24%), ARID1A (21%), BAP1 (15%), KRAS (13%), PBRM1 (12%), SMAD (9%), ATM (8%), BRAF (<5%) and MSI-H (0.5%) are the most commonly mutated genes in CCA [13]. Biliary tract cancer reveals molecular heterogeneity and there is a crucial need to identify a subset of patients who can benefit from targeted therapy to be used after progression on first-line treatment gemcitabine plus cisplatin [34]. The ClarIDHy study showed that ivosidenub significantly improved PFS, with a trend towards favorable overall survival, in comparison to placebo in patients with advanced cholangiocarcinoma carrying an IDH1 mutation [35]. At ASCO GI 2019, Park et al. presented encouraging preliminary results on the efficacy of erdafitinib in FGFR-mutated CCA patients as a second-line therapy (NCT 02699606). Andersen et al. reported that BRAF V600E occurs with the highest frequency in ICC (1.5%) and is associated with poor prognosis [36]. Focusing on biliary tract cancer, preliminary data from the ROAR basket trial demonstrated promising activity of dabrafenib plus trametinib with a favorable safety profile in patients with BRAF V600E (ROAR trial; NCT 02034110).
Based on all these results, we decided to administer a combination of MEK and BRAF inhibitors in a patient with BRAF mutant, chemotherapy-refractory ICC and obtained results in line with the few cases reported in literature. Lavingia et al. described two cases reaching 9 and 12 months PFS when treated with dabrafenib and trametinib [37]. Bunyatov et al. showed the longest remission with the same combination: a full response after 7 months of treatment with complete remission lasting 28 months [38]. In the second case, the PDX model predicted clinical response to dabrafenib and trametinib. BDC is a rare subtype of renal cell carcinoma with an extremely poor prognosis. Given the rarity of BDC and therefore the scarcity of specific clinical trials, the best treatment for this tumor remains uncertain. The only combination of cytotoxic agents which shows effectiveness is gemcitabine plus platinum [39]. Oudard et al. showed a 26% objective response in BDC with the gemcitabine plus platinum salt regimen used as a first-line treatment [40]. Furthermore, recent data also suggest a role for anti-angiogenic therapy in this setting. Péchuchet et al. demonstrated that addition of bevacizumab to platinum-based chemotherapy in previously untreated BDC patients resulted in longer PFS and OS, with a manageable safety profile [41]. In his BDC case report, El Mehdi Tazi et al. demonstrated a therapeutic response to sunitinib [42] and Ansari J et al. showed similar results with sorafenib [43]. Unfortunately, clinical trials failed to show activity of any targeted drugs [44]. Sharing common morphological and biological characteristics with urothelial carcinomas, to date, chemotherapy remains the standard treatment for patients with BDC. Nevertheless, after progression with first-line chemotherapy, the second-line approach still presents a challenge, and patient outcome remains poor. For this reason and on the basis of the genomic sequencing results, with the presence of a BRAF G466A mutation, we decided to use the combination of anti-BRAF and anti-MEK treatment. G466A belongs to Class 3 BRAF mutations depending on RAS signaling: thus, blocking RAS signaling would appear to be a potential therapeutic strategy for class 3 BRAF-mutant tumors, but to date there are no specific inhibitors available [45].
4. Conclusions
In the last few years, there have been increasing efforts to understand the molecular biology of several rare tumors with limited treatment options. Genome analysis could, in these cases, help find specific genomic alterations which can be targeted. Precision medicine allows a personalized approach based on biomarker individualization [46].
The approval of the first-in-class tumor agnostic therapies shows that identification of biomarkers independent from tumor origin could offer new treatment options with drugs already on the market [47].
In the literature, there is strong evidence that different tumors with BRAF mutations are good targets for BRAF/MEK pathway inhibitors and our work adds to this evidence.
This report highlights the importance of molecular profiling for the management of solid tumors, and more specifically, orphan tumors. In the era of precision medicine, patients with otherwise very grim expectations can benefit from such approaches while we wait for more prospective studies to provide evidence.
Acknowledgments
The authors express sincerest gratitude to the two patients and their families, the medical staff of doctors, nurses, scientists, health and administrative personnel for the strenuous work in such a delicate moment for healthcare.
Author Contributions
Conceptualization, D.G.; investigation, O.B., C.S., M.M., and D.G.; resources, M.R.C., G.F., N.Z., V.C. and A.M.; data curation, O.B. and M.S.; writing—original draft preparation, O.B. an M.S.; writing—review and editing, S.P.C. and G.R.; supervision, D.G.; project administration, D.G.; funding acquisition, D.G. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by MEDnoTE srl (Spin-off—University of Trieste).
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of ATS Val Padana (protocol code 42998 approved on 21 december 2018).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Data is available from the authors upon request.
Conflicts of Interest
DG reports personal fees for consulting, advisory role and speakers’ bureau from Novartis, Pfizer, Lilly; fees for travel and accommodations from Novartis, Pfizer, Lilly. Other authors have no potential conflicts of interest to disclose.
Ethical Approval and Consent to Participate
All patients signed the informed consent related to the Mozart protocol. We obtained the Local Ethics Committee Val Padana approval related to the Mozart protocol (code 42998) on the 21 December 2018. The Mozart protocol is a program to understand the molecular aberrations related resistance/responsiveness to novel drugs in metastatic solid tumors.
Figure 1 (a) CT scan, March 2019; (b) CT scan, September 2020.
Figure 2 FDG-PET after 4 weeks of treatment with dabrafenib and trametinib showed decreased FDG avidity. (a) FDG-PET performed in January; (b) FDG-PET performed in February 2016.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Oral | DrugAdministrationRoute | CC BY | 33669326 | 19,897,628 | 2021-02-16 |
What was the dosage of drug 'GEMCITABINE HYDROCHLORIDE'? | Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature.
BACKGROUND
Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy. The disease remained under control for 11 months after the first relapse.
CONCLUSIONS
In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors.
CONCLUSIONS
Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with.
1. Introduction
Over the past decade, tumor molecular profiling has been widely applied, leading to an individualized approach for patients termed “personalized” or “precision medicine”. This new approach has replaced the standard chemotherapy treatment based on the tumor’s origin, histology and nodal invasion (TNM) [1]. The aim of precision medicine is to define treatment based upon genomic drivers of tumorigenesis, thus identifying the best therapy for patients [2]. Moreover, precision oncology assesses tumor response to a specific treatment and finds drug resistance when it occurs [3].
The BRAF mutant is an oncogenic driver, since BRAF inactivation slows down systemic tumor growth and induces cancer cell toxicity [4]. BRAF is a member of the Raf kinase family and plays a critical role in cellular growth, proliferation and differentiation through the MAP-kinase (MAPK) pathway [5].
The Cancer Genome Atlas (TCGA) has identified BRAF mutations in many different cancer types: 60% of melanomas, 60% of thyroid cancers, 15% of colorectal cancers, and 5–8% of non-small cell lung cancers [6]. Moreover, mutations in this gene are present in diffuse gliomas, cholangiocarcinoma, hairy cell leukemia, multiple myeloma, Langerhans cell histiocytosis and Erdheim–Chester disease [7].
Around 200 BRAF mutant alleles and 30 mutations of BRAF have been identified and characterized and V600E is the most common mutation [8]. BRAF mutations can be classified into three classes: class 1 and 2 are RAS-independent, while class 3 depends on RAS signaling [9].
Pembrolizumab and nivolumab for patients with high levels of microsatellite instability and deficient DNA mismatch repair (dMMR), and larotectinib for tropomyosin receptor kinases (TRK), have introduced the concept of tumor type agnostic therapy [10] where genomic alterations could be used to drive tumor therapy, regardless of tumor origin [11].
On the basis of this concept, in this report we describe two case studies in which treatment decisions have been driven by next generation sequencing (NGS). The first case study is that of a 59-year-old Caucasian man with BRAF V600E mutated intrahepatic cholangiocarcinoma (ICC). Intrahepatic cholangiocarcinoma is the second most common hepatic cancer and its incidence is increasing worldwide [4]. One of its targetable alterations is a v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation. While BRAF mutations are rare in pancreato-biliary cancers, they are reported with higher frequency, about 5% of all cases, in ICC [12]. The majority of mutations occur at the V600 position, with V600E observed in 5% of cholangiocarcinoma (CCA) [13].
The second case study is that of a 50-year-old, Caucasian woman, with BRAF G466A mutated Bellini duct carcinoma (BDC). BDC is a very rare and aggressive variant of kidney carcinoma, arising from the renal medulla, possibly from the distal collecting ducts of Bellini [14]. BDC is characterized by an aggressive clinical course and an extremely poor prognosis [15]. Less than one-third of patients survive more than 2 years after diagnosis, and in most reported cases metastatic disease is present ab initio. Radical nephrectomy is generally performed, followed by medical treatments such as immunotherapy, targeted therapies or chemotherapy [16]. Given the rarity of this cancer, it has been difficult to conduct large-scale clinical trials and a specific standard treatment has not yet been established.
These clinical cases may represent a proof of concept of how identifying and targeting potential molecular drivers, such as BRAF mutations, independently of tissue origin, could provide represent therapeutic opportunities, especially for rare cancers.
2. Case Presentation
2.1. Case 1
A 59-year-old Caucasian male patient, with metabolic syndrome and type 2 diabetes, was admitted to the emergency department in January 2017 with severe hip pain, nausea and increasing discomfort. Abdominal ultrasound and computerized axial tomography showed the presence of a 6 × 9 cm hepatic nodule in the VI segment. In February 2017 the patient underwent VI hepatic segment resection and cholecystectomy. Immunohistochemistry revealed moderately differentiated CCA, positive for CK7, CK19 and CA19, and negative for CK20. The patient was diagnosed with cT2aN0M0 disease. Indication to standard follow-up was given due to the absence of resection margins and lymph node involvement. However, in September 2017, after seven months of follow-up, positron emission tomography (PET) showed hyperfixation of the ischio-pubic branch and sacro-iliac articulation. The subsequent ischio-pubic biopsy revealed cholangiocarcinoma metastasis. At this point, first line chemotherapy with cisplatin (25 mg/m2) and gemcitabine (1000 mg/m2) on day 1 and 8 every 3 weeks was administered for 6 cycles. Furthermore, palliative radiotherapy was performed on the bone metastasis (20 Gy in fraction 5). After 6 cycles of chemotherapy, CT scans showed hepatic, lung, lymphonodal and bone disease progression. In June 2018, after multidisciplinary discussion, the patient started a second line chemotherapy with oxaliplatin (130 mg/m2) on day 1 and capecitabine (1000 mg/m2) orally BID for 14 days every 3 weeks, without clinical and radiological response.
In light of tumor resistance to second line chemotherapy, primary tumor next generation sequencing was performed in January 2019, which showed the presence of a BRAF V600E mutation. Given this result, it was decided to start off-label use of vemurafenib (960 mg/day) and cobimetinib (60 mg/day). During the course of this therapy, he remained almost completely asymptomatic, with the exception of some episodes of grade 2 nausea and self-limiting skin rash, which occurred during the first month. Biochemical evaluations showed an increase in alkaline phosphatase and blood creatine phosphokinase during the first and second month, respectively. Six months after beginning targeted therapy, restaging CT scans reported a treatment response, with an additional reduction of pulmonary nodules and hepatic lesions. Furthermore, the bone lesions appeared sclerotic due to treatment response. His last CT scan was performed in September 2020 and confirmed stable disease (Figure 1). To date, the patient is still on treatment.
In addition, EORTC QLQ-C30 (a standardized quality of life questionnaire) was conducted both at the beginning of treatment and after the latest radiological evaluation, revealing a progressive improvement in physical functioning (essential abilities for maintaining independence) and role functioning (abilities for work/leisure). Moreover, the patient has gradually reduced opioid intake until complete suspension.
2.2. Case 2
In January 2015, a 50-year-old, Caucasian woman, without comorbidities, was admitted to our hospital with a painless gross hematuria lasting 3 months. Physical examination revealed a percussion pain over the left kidney region and no extrarenal manifestations were found at clinical and laboratory examinations. A kidney tumor was suspected on the basis of the urinary system ultrasonography and the finding was subsequently confirmed with a total body CT scan. The imaging revealed a 3 × 3.5 cm heterogeneous enhancing mass, in the middle pole of the left kidney, which was further compounded with multiple metastases in the retroperitoneal lymph nodes, ovaries and a 12 mm temporal lobe brain lesion without perilesional edema. The patient subsequently underwent laparoscopic nephroureterectomy.
The final pathological report showed Bellini duct carcinoma (BDC) of the left kidney, Fuhrman Nuclear Grade IV. The histological diagnosis of BDC was confirmed by positive immunohistochemical staining with UEA-1 and EMA, and negative staining with Leu-M1 [17]. According to the American Joint Committee on Cancer (AJCC) 2015 classification and TNM classification, the patient was diagnosed with a high-grade, stage 4 disease.
After multidisciplinary discussion, in February 2015, the patient started first line chemotherapy with bevacizumab (15 mg/kg) and gemcitabine (1250 mg/m2) on days 1 and 8 and platinum salt (cisplatin 80 mg/m2 or carboplatin AUC 5 mg/ml/min) every 3 weeks. After 3 cycles, she obtained a clinical response and a CT scan showed partial radiological response. At this stage, one of the ovarian metastasis was resected in order to create a patient-derived xenograft (PDX). At the end of the 5th cycle, she developed febrile neutropenia (neu < 500/mm3). In light of the hematological toxicity, the chemotherapy was stopped while maintaining bevacizumab every 3 weeks. Maintenance therapy was well tolerated. Furthermore, stereotaxic radiotherapy was performed on the brain metastasis (24 Gray in 2 fractions).
After 6 cycles of maintenance bevacizumab (December 2015), retroperitoneal lymph node disease progressed. Using the PDX mouse-derived model, we were able to perform a mutational analysis.
Genomic sequencing of the ovarian metastasis revealed a BRAF G466A mutation. Hence, a therapeutic combination of trametinib and dabrafenib was started. After one month of therapy, the patient developed pyrexia and rash treated with common medications; however, the 18F-FDG-PET/CT performed at the beginning of treatment and repeated after 4 weeks showed decreased FDG avidity in the ovary and lymph node metastases (Figure 2).
From January 2016 to December 2016 the patient showed stable disease. However, in January 2017, she was admitted to the emergency department complaining of headaches, nausea and dizziness; her performance status worsened to 3, requiring the patient to be hospitalized. Brain CT scans revealed multiple metastases in the frontal, parietal and temporal lobe bilaterally, further confirmed by MRI. After one week, the patient passed away due to widespread brain metastasis. The disease was under control for 11 months after the first relapse.
3. Discussion
In 2011, the Food and Drug Administration approved the BRAF inhibitor vemurafenib for the treatment of BRAF V600E mutant metastatic melanoma [18]. Dabrafenib, another BRAF inhibitor, obtained FDA approval in 2013 [19]. In the coBRIM trial, Larkin J et al. demonstrated that the combination of vemurafenib with the MEK inhibitor cobimetinib resulted in significant progression-free survival (PFS) improvement among patients with BRAF V600E mutated metastatic melanoma in comparison to the combination of vemurafenib with placebo [20]. More recent studies showed that combining BRAF and MEK inhibitors determines a PFS improvement from a median of 7 months to 12 months in this setting [21]. Furthermore, the combination of MEK and BRAF inhibitors can decrease the onset of resistance to treatment and side effects that arise during BRAF inhibitor monotherapy [22]. This combination reduces the incidence of skin toxicity, including cutaneous squamous carcinoma associated with BRAF inhibition [23]. In mutated cells, B-raf protein is found in its hyperactive form. Combined BRAF inhibitors block the Ras-Raf-MEK-MAPK kinase pathway, but, as it happens with monotherapy, pharmacological resistance may develop after 6–7 months of treatment. To overcome this resistance, BRAF inhibitors are used in combination with MEK inhibitors which mediate the blockade of MAPK kinase (MEK), downstream of BRAF in the MAPK pathway [24]. Beside melanoma, thyroid cancers [25] and colon cancers [26], the prevalence of a BRAF V600E mutation in other cancers is less than 5% [27]. The relatively low frequency of this mutation accounts for the lack of randomized controlled studies looking at the use of specific anti-BRAF targeted therapies in other cancers. This difficulty is even true in the case of very rare tumors such as CCA and BDC, so that tumor-specific studies are almost impossible to run. On the other hand, the lack of therapeutic options for these rare diseases provides a strong rationale for targeting putative driver mutations.
To address such paradoxes, basket trials have come to the rescue, putting together tumors with different histology, on the basis of their molecular landscapes and, more specifically, the presence of a BRAF V600E mutation [28]. Whilst this approach still has limitations, such as the small number of patients enrolled per tumor type, and therefore there is low statistical power in the studies, some important indications can be drawn from them. Hyman et al. report results from a basket trial including a total of 122 patients with BRAF V600E mutation-positive cancers [29]. The primary end point of the study was the response rate; secondary end points were progression-free survival and overall survival. As the response varied across tumor types, the authors concluded that BRAF V600E mutation is certainly targetable in many, but not all, cancers, and that perhaps the tumor site in which they develop are important in determining the degree of response to a specific targeted therapy. The study had 6 tumor cohorts plus an “all other cancers” cohort. Clinical activity, including some complete responses, was observed in NSCLC, Langerhans cell histiocytosis, anaplastic thyroid cancer, ovarian cancer and cholangiocarcinoma. Colon cancer patients did not show any response to vemurafenib single-agent therapy and even when the anti-BRAF therapy was combined with cetuximab the results were not encouraging. These patients were however heavily pretreated, having had 1 to 6 previous lines of therapy [29]. The contribution of mutated BRAF seems to change amongst tumor types, as suggested by the very heterogeneous results in terms of clinical benefit of BRAF inhibition in different cancers. For instance, this mutation alone may not sufficient to drive tumor progression in certain tumor types, such as colon cancer [30].
Thus, the question of whether all BRAF-mutated cancers are amenable to specific targeted therapy is still open. Perhaps, extremely rare tumors and orphan cancers, where proven effective treatment strategies are lacking, could benefit by even modest therapeutic activity. Cholangiocarcinoma is one of the most aggressive biliary tract malignancies [31]. After first-line therapy, no standard second-line treatment has been established yet and the outcome remains rather poor, with a 5-year overall survival rate of around 2% due to metastatic disease [32]. Data from the literature show that nearly 35% of CCA harbor potentially targetable genomic alterations and the use of molecular profiling has led to the discovery of potential disease drivers [33]. Lowery MA et al. showed that IDH1 (25%), TP53 (24%), ARID1A (21%), BAP1 (15%), KRAS (13%), PBRM1 (12%), SMAD (9%), ATM (8%), BRAF (<5%) and MSI-H (0.5%) are the most commonly mutated genes in CCA [13]. Biliary tract cancer reveals molecular heterogeneity and there is a crucial need to identify a subset of patients who can benefit from targeted therapy to be used after progression on first-line treatment gemcitabine plus cisplatin [34]. The ClarIDHy study showed that ivosidenub significantly improved PFS, with a trend towards favorable overall survival, in comparison to placebo in patients with advanced cholangiocarcinoma carrying an IDH1 mutation [35]. At ASCO GI 2019, Park et al. presented encouraging preliminary results on the efficacy of erdafitinib in FGFR-mutated CCA patients as a second-line therapy (NCT 02699606). Andersen et al. reported that BRAF V600E occurs with the highest frequency in ICC (1.5%) and is associated with poor prognosis [36]. Focusing on biliary tract cancer, preliminary data from the ROAR basket trial demonstrated promising activity of dabrafenib plus trametinib with a favorable safety profile in patients with BRAF V600E (ROAR trial; NCT 02034110).
Based on all these results, we decided to administer a combination of MEK and BRAF inhibitors in a patient with BRAF mutant, chemotherapy-refractory ICC and obtained results in line with the few cases reported in literature. Lavingia et al. described two cases reaching 9 and 12 months PFS when treated with dabrafenib and trametinib [37]. Bunyatov et al. showed the longest remission with the same combination: a full response after 7 months of treatment with complete remission lasting 28 months [38]. In the second case, the PDX model predicted clinical response to dabrafenib and trametinib. BDC is a rare subtype of renal cell carcinoma with an extremely poor prognosis. Given the rarity of BDC and therefore the scarcity of specific clinical trials, the best treatment for this tumor remains uncertain. The only combination of cytotoxic agents which shows effectiveness is gemcitabine plus platinum [39]. Oudard et al. showed a 26% objective response in BDC with the gemcitabine plus platinum salt regimen used as a first-line treatment [40]. Furthermore, recent data also suggest a role for anti-angiogenic therapy in this setting. Péchuchet et al. demonstrated that addition of bevacizumab to platinum-based chemotherapy in previously untreated BDC patients resulted in longer PFS and OS, with a manageable safety profile [41]. In his BDC case report, El Mehdi Tazi et al. demonstrated a therapeutic response to sunitinib [42] and Ansari J et al. showed similar results with sorafenib [43]. Unfortunately, clinical trials failed to show activity of any targeted drugs [44]. Sharing common morphological and biological characteristics with urothelial carcinomas, to date, chemotherapy remains the standard treatment for patients with BDC. Nevertheless, after progression with first-line chemotherapy, the second-line approach still presents a challenge, and patient outcome remains poor. For this reason and on the basis of the genomic sequencing results, with the presence of a BRAF G466A mutation, we decided to use the combination of anti-BRAF and anti-MEK treatment. G466A belongs to Class 3 BRAF mutations depending on RAS signaling: thus, blocking RAS signaling would appear to be a potential therapeutic strategy for class 3 BRAF-mutant tumors, but to date there are no specific inhibitors available [45].
4. Conclusions
In the last few years, there have been increasing efforts to understand the molecular biology of several rare tumors with limited treatment options. Genome analysis could, in these cases, help find specific genomic alterations which can be targeted. Precision medicine allows a personalized approach based on biomarker individualization [46].
The approval of the first-in-class tumor agnostic therapies shows that identification of biomarkers independent from tumor origin could offer new treatment options with drugs already on the market [47].
In the literature, there is strong evidence that different tumors with BRAF mutations are good targets for BRAF/MEK pathway inhibitors and our work adds to this evidence.
This report highlights the importance of molecular profiling for the management of solid tumors, and more specifically, orphan tumors. In the era of precision medicine, patients with otherwise very grim expectations can benefit from such approaches while we wait for more prospective studies to provide evidence.
Acknowledgments
The authors express sincerest gratitude to the two patients and their families, the medical staff of doctors, nurses, scientists, health and administrative personnel for the strenuous work in such a delicate moment for healthcare.
Author Contributions
Conceptualization, D.G.; investigation, O.B., C.S., M.M., and D.G.; resources, M.R.C., G.F., N.Z., V.C. and A.M.; data curation, O.B. and M.S.; writing—original draft preparation, O.B. an M.S.; writing—review and editing, S.P.C. and G.R.; supervision, D.G.; project administration, D.G.; funding acquisition, D.G. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by MEDnoTE srl (Spin-off—University of Trieste).
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of ATS Val Padana (protocol code 42998 approved on 21 december 2018).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Data is available from the authors upon request.
Conflicts of Interest
DG reports personal fees for consulting, advisory role and speakers’ bureau from Novartis, Pfizer, Lilly; fees for travel and accommodations from Novartis, Pfizer, Lilly. Other authors have no potential conflicts of interest to disclose.
Ethical Approval and Consent to Participate
All patients signed the informed consent related to the Mozart protocol. We obtained the Local Ethics Committee Val Padana approval related to the Mozart protocol (code 42998) on the 21 December 2018. The Mozart protocol is a program to understand the molecular aberrations related resistance/responsiveness to novel drugs in metastatic solid tumors.
Figure 1 (a) CT scan, March 2019; (b) CT scan, September 2020.
Figure 2 FDG-PET after 4 weeks of treatment with dabrafenib and trametinib showed decreased FDG avidity. (a) FDG-PET performed in January; (b) FDG-PET performed in February 2016.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 1250 MG/M2, CYCLIC ON DAYS 1 AND 8 | DrugDosageText | CC BY | 33669326 | 19,768,778 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anticoagulation drug level above therapeutic'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anticoagulation drug level increased'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Confusional state'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease recurrence'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastric occult blood positive'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal haemorrhage'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haematoma infection'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhage'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyponatraemia'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nephropathy'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | RIVAROXABAN | DrugsGivenReaction | CC BY | 33669373 | 19,272,482 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Normocytic anaemia'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal impairment'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Septic shock'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Subcapsular renal haematoma'. | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | BISOPROLOL, DABIGATRAN ETEXILATE MESYLATE, INSULIN NOS, LEVOTHYROXINE, MEMANTINE, ROSUVASTATIN, WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the administration route of drug 'DABIGATRAN ETEXILATE MESYLATE'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Oral | DrugAdministrationRoute | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the administration route of drug 'RIVAROXABAN'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Oral | DrugAdministrationRoute | CC BY | 33669373 | 19,280,908 | 2021-02-16 |
What was the administration route of drug 'WARFARIN SODIUM'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Oral | DrugAdministrationRoute | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the dosage of drug 'DABIGATRAN ETEXILATE MESYLATE'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | 110 mg (milligrams). | DrugDosage | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the outcome of reaction 'Acute kidney injury'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Recovering | ReactionOutcome | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the outcome of reaction 'Anticoagulation drug level above therapeutic'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Recovering | ReactionOutcome | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the outcome of reaction 'Anticoagulation drug level increased'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Recovering | ReactionOutcome | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the outcome of reaction 'Blood creatinine increased'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Recovering | ReactionOutcome | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the outcome of reaction 'Condition aggravated'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Fatal | ReactionOutcome | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the outcome of reaction 'Gastric occult blood positive'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Recovering | ReactionOutcome | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the outcome of reaction 'Haematoma infection'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Fatal | ReactionOutcome | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the outcome of reaction 'Nephropathy'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Recovering | ReactionOutcome | CC BY | 33669373 | 19,272,482 | 2021-02-16 |
What was the outcome of reaction 'Normocytic anaemia'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Recovering | ReactionOutcome | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the outcome of reaction 'Renal impairment'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Recovering | ReactionOutcome | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the outcome of reaction 'Renal tubular injury'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Recovering | ReactionOutcome | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
What was the outcome of reaction 'Septic shock'? | Management of Anticoagulant-Related Nephropathy: A Single Center Experience.
BACKGROUND
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
METHODS
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
RESULTS
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
CONCLUSIONS
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
1. Introduction
Anticoagulant-related nephropathy (ARN) is a recently recognized form of acute kidney injury (AKI) that is associated with rapid deterioration of kidney function and a substantially decreased survival rate [1,2]. It was first described as a complication of warfarin treatment related to an abnormal international normalized ratio (INR) characterized by glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [3]. However, an abnormally elevated INR does not always cause ARN and pre-existing renal damage is required in addition to excessive anticoagulation [4]. Because renal biopsy is not performed in most cases that are overly anticoagulated, the diagnosis is often presumptive, and the prevalence of the disease is probably greatly underestimated.
In recent years, warfarin has been partially replaced by direct oral anticoagulants (DOACs), which inhibit thrombin or factor Xa, the key proteases in the coagulation cascade. Recent reports show that, apart from warfarin, DOACs, particularly dabigatran, 85% of which is excreted through the kidneys, are also associated with ARN [5,6,7]. We present here a case of ARN related to dabigatran and warfarin, a retrospective analysis of patients with ARN in our country, and a review of the current literature.
2. Presentation of the Representative Case
An 82-year-old woman with a history of arterial hypertension, insulin-dependent diabetes mellitus type 2, hypothyroidism, cognitive decline, and chronic kidney disease (CKD) with a creatinine baseline value of 124 µmol/L and microscopic hematuria was admitted to the nephrology department because of AKI. Her creatinine level increased to 373 µmol/L, and urinalysis showed gross hematuria. She had signs of normocytic anemia. Her daily medication included levothyroxine, memantine, bisoprolol, rosuvastatin, and insulin. Eighteen days previously, dabigatran had been introduced at a dose of 110 mg bd due to a new onset of atrial fibrillation and a transient ischemic attack in her medical history. Laboratory, immunology, and imaging findings at admission are presented in Table 1.
Since gross hematuria and occult gastrointestinal bleeding were present, dabigatran was discontinued immediately. The serum concentration of dabigatran was highly elevated (650 µg/L). However, she was not treated with idarucizumab (reversal agent for dabigatran) since the bleeding was not considered life-threatening. Due to a further decrease of renal function and a high concentration of dabigatran (446 µg/L), dialysis was started. Eight dialysis procedures altogether were necessary to decrease the level of dabigatran to within the reference range (Figure 1). The thrombin time was also significantly reduced, from over 150 s, measured at admission, to 21.9 s (reference range below 21 s).
Common urological causes of macroscopic hematuria were ruled out. A kidney biopsy was performed after normalization of the coagulation times. It showed signs of ARN with occlusive intratubular RBC casts, diffuse acute tubular injury, and diffuse interstitial edema, together with mild IgA nephropathy (IgAN) (Figure 2).
After the introduction of methylprednisolone (at the time-point when the patient had been dialysis-dependent for more than three weeks), kidney function gradually improved, and dialysis treatment was discontinued. Four weeks after discharge, creatinine dropped to 210 µmol/L and hematuria was markedly reduced. Methylprednisolone was gradually tapered down. Because of advanced CKD and an 11.2% risk of stroke per year (CHA2DS2-VASc score = 7), warfarin was introduced. Six months later, the patient was readmitted due to an acute decrease in kidney function and gross hematuria, this time associated with a supratherapeutic INR (4.23). Dialysis was re-started. In addition, the patient was diagnosed with a subcapsular hematoma of the left kidney (which occurred at the puncture site of a renal biopsy performed six months earlier) and required urgent embolization of a segmental artery. In the period following embolization, the patient’s clinical condition worsened, with infection of the renal subcapsular hematoma and septic shock, leading to death. An autopsy was not performed.
3. Patients and Methods
This presented case prompted us further to investigate cases of ARN at a national level. We therefore reviewed the medical records of our national database of kidney biopsies, consisting of 1960 native kidney biopsies over the last seven years (since our first recognized case of ARN) and updated the series with 13 cases altogether (Table 2 and Table 3). The methodology of search and analysis of selected reports in the national kidney biopsy database is presented in the Supplementary Materials.
To gain a broader insight into the global knowledge of ARN and to have the opportunity to compare the characteristics of our cohort with others, we also reviewed the global literature reported from the first mention of the disease in 2009 until 2019, including individual case reports, case series, and cohort studies. Electronic searches were conducted in the PubMed database using key words and their combinations: “anticoagulant, nephropathy, warfarin, DOAC, NOAC, CKD” (Supplementary Tables S2 and S3).
4. Results
4.1. Clinical Features
The 13 patients (eight men and five women) with ARN in our national cohort averaged 70 years of age and had presented with gross hematuria (n = 11) or microscopic hematuria (n = 2) and acute decline of kidney function (n = 13) at various time-periods after the initiation of anticoagulant therapy (Table 2). A greater acute increase in serum creatinine of more than 25% from baseline was seen in 9 of 13 patients (69.2%). The anticoagulant was warfarin or acenocoumarol in seven cases, dabigatran and warfarin in one case (the presented case), dabigatran in two cases, rivaroxaban in two cases, and low molecular weight heparin (LMWH) in one case. The anticoagulant therapy was excessive in seven patients (according to INR, the concentration of dabigatran or anti-Xa-rivaroxaban). In two patients, ARN occurred late after the introduction of warfarin (10 and 15 years, respectively), in both cases associated with severe over-anticoagulation. In six patients, the indication for anticoagulation was atrial fibrillation, in four patients, a mechanical cardiac valve, and in three cases, other causes. All patients had comorbidities, including an underlying kidney disease, which was advanced glomerulosclerosis in one case, latent IgA deposits and a thin glomerular basement membrane in one case, and IgAN in 11 cases, as confirmed by the kidney biopsy.
4.2. Histopathological Features
Renal biopsies from all patients with ARN showed acute tubular injury of varying intensity, including severe, moderate/severe, moderate, mild/moderate, or mild acute tubular injury (one, one, three, six, and two patients, respectively; Table 3). Eleven patients showed diffuse tubular injury, whereas only focal mild tubular injury was found in two patients. All patients presented with occlusive intratubular RBC casts without the Tam Horsfall protein in an average of 7.1% of the tubules (range 2–20.3%), which were mainly found in the distal tubules and therefore appeared to be more common in the medulla than in the cortex. Medulla was collected in 11 of 13 patients. There was no regurgitation of the Tam Horsfall protein in the urinary space of the glomeruli in any patient. In 11 of 13 cases, a diagnosis of IgAN was made, and in one case (no. 6), we observed a thin glomerular basement membrane and mesangial IgA deposition without C3 deposits. It is known that up to 16% of the healthy population have latent mesangial IgA deposits without clinical manifestations [8]. According to the Oxford classification, in all diagnosed cases of IgAN, the disease was mild with only focal mild segmental mesangial proliferation and no endocapillary or extracapillary proliferation (M0, E0, S0, C0, whereas T was not evaluated due to diffuse acute tubular injury unrelated to IgAN). In only one patient (no. 8, Table 2), there was one small fibrocellular crescent in 1 of 17 glomeruli, consistent with the Oxford classification M0, E0, S0, C1. In addition, the disease course before the episode of ARN was generally subclinical. All patients with ARN showed extensive changes in the tubulointerstitial compartment (tubular injury and occlusive intratubular RBC casts), unrelated to relatively mild active glomerular changes or glomerulosclerosis.
4.3. Treatment and Outcome
Details of the clinical course and treatment are presented in Table 2.
In six cases treated with anticoagulants for atrial fibrillation (patients no. 2, 3, 6, 7, 8, 9) and in two cases of post thrombotic events (patients no. 12, 13), the precipitating anticoagulant was discontinued immediately after admission. In four patients treated with warfarin or acenocoumarol for a mechanical heart valve, the excessive anticoagulant effect was reversed with vitamin K, and there was a temporary switch to heparin. Other anticoagulation reversal agents (i.e., idarucizumab for dabigatran or recombinant coagulation factor Xa for apixaban and rivaroxaban) were not used. None of our patients with ARN were treated with N-acetyl-cysteine.
Kidney biopsy was performed at a median time of 13 days after admission (range of 1 to 39 days), when safe conditions for the invasive procedure were present. Adequate reversal of anticoagulation was achieved in 14.5 ± 14.3 days (median 6.5 days) after admission in patients treated with coumarins, and in 17 ± 5.8 days (median 19 days) in patients treated with DOACs.
After histologic evidence of ARN (on average, 2 to 3 days after kidney biopsy), methylprednisolone was introduced in eight patients, with an initial dose of 0.4–0.8 mg/kg body weight (some patients initially received pulses of steroids), which was tapered over 6 to 8 weeks.
All patients treated with steroids initially had more severe acute kidney injury, with an average increase in serum creatinine of 239.5% (range 46.5 to 489.3%) compared to an average increase of 15.82% (range 12.5 to 20.5%) in patients who were clinically judged to have no need for steroid therapy (please note that in patients no. 5 and 11, with a severe form of ARN, corticosteroid treatment was considered, but they were not treated due to the drawbacks listed below). All but one patient (no. 6) treated with steroids presented with macrohematuria. Retrospective re-evaluation of the kidney biopsy specimens revealed that the steroid-treated patients had a histologic picture of more severe acute kidney injury, including 70–100% of tubules with evidence of acute tubular injury, 40–100% interstitial edema, and an average of 9.4% of tubules filled with RBC casts. Interstitial infiltrate was rare and present in only up to 10% of the sample. In patients treated with steroids, renal function improved markedly at the time of the last follow-up compared to the time of diagnosis.
Five patients (patients no. 3, 5, 10, 11, 13) were not treated with steroids. According to our clinical judgement, three of them lacked indication since complete restitution of mild renal dysfunction and regression of hematuria was achieved after discontinuation of anticoagulant therapy. One patient was not further treated because of already advanced glomerulosclerosis with no prospect of improvement (patient no. 5) and one had contraindications for steroids associated with comorbidities, such as an aortic stent graft infection (patient no. 11). In the three patients who presented with mild AKI and hematuria (one had microscopic hematuria and two had macrohematuria), histologic reevaluation showed a mild degree of acute tubular injury with 20–50% injured tubules, with up to 10% interstitial infiltrate and 5–25% interstitial edema. RBC casts were detected in an average of 3.9% of tubules.
A total of two patients required supportive therapy with dialysis during follow-up, including patient no. 9 (case presented), whose kidney function improved after therapy with methylprednisolone, and patient no. 5, who developed end-stage renal failure and required maintenance dialysis. One patient died due to infectious complications (case presented). No serious adverse effects were reported in the other steroid-treated patients.
Bringing together our clinical and pathological findings with the previously reported experiences of other groups [9,10,11], we propose a useful clinicopathological algorithm to address ARN (Figure 3).
5. Discussion
Almost half a century has passed since an Australian scientific group led by Dr. Kincaid-Smith attempted to treat IgAN with the famous triple therapy known as the Melbourne Cocktail [12]. The triple therapy, which consisted of cyclophosphamide, antiplatelet dipyridamole and warfarin in full anticoagulant doses, would probably be considered controversial today. It proved effective in reducing proteinuria, but patients experienced worsening of renal function with more glomerular bleeding, as evidenced by increased urinary RBC counts compared to the control group [13].
Although this old study did not provide a revolutionary solution for our most common nephropathy, it inadvertently led to hemorrhagic adverse effects, which were not recognized until much later as being associated with warfarin (and possibly also dipyridamole). Namely, in 2009, Brodsky et al. [3] were the first to present a case series of nine patients with unexplained AKI and hematuria while on warfarin therapy. All patients included in this retrospective study had underlying kidney disease, the most common being IgAN, followed by diabetic nephropathy, lupus glomerulonephritis, focal segmental glomerulosclerosis, and nephrosclerosis [3]. Since the publication of this case series, unexplained AKI, together with excessive anticoagulation and specific renal biopsy findings with glomerular hemorrhage and occlusive RBC casts, has been defined as warfarin-related nephropathy [2]. In recent years, it has been recognized that DOACs, and even antiplatelets can also cause this type of kidney injury, and the term anticoagulant-related nephropathy (ARN) is now widely used.
By way of introduction, we present an illustrative case of a patient with recurrent ARN that initially occurred after anticoagulation with dabigatran and later recurred after DOAC was replaced with warfarin. In both cases, ARN was related to excessive anticoagulation. The patient had preexisting IgAN presenting as microscopic hematuria and renal insufficiency with an eGFR of 35 mL/min/1.73 m2, which seriously approached the limit at which dabigatran is contraindicated (i.e., an eGFR < 30 mL/min/1.73 m2). Histologic examination revealed diffuse acute tubular injury along with occlusive tubular RBC casts, consistent with ARN (Figure 2). Although dabigatran was immediately discontinued, its anticoagulant effects persisted due to severe accumulation, which maintained macrohematuria and delayed the time to kidney biopsy. The patient successfully overcame the period of renal failure with hemodialysis, which also reduced (by increasing drug excretion) the risk of life-threatening bleeding. Steroid treatment, initiated after the patient had been dialysis-dependent for more than three weeks without recovery of renal function, was considered successful in providing rapid improvement in renal function. However, the patient subsequently succumbed to sepsis, and immunosuppressive therapy may have played a role in this.
Since there are still no guidelines for the management of ARN, and in order to assess this area comprehensively, we analyzed our national cases of ARN since our first case in 2014 (Table 2 and Table 3) and reviewed the international literature reported to date (Supplementary Table S2 and Table S3). Based on our experience and including suggestions previously put forward by others [9,10,11], we propose an algorithm of diagnostic–therapeutic steps required in patients with suspected ARN (Figure 3).
In accordance with the characteristics of our national patient cohort, the most common underlying kidney disease in patients with ARN at the global level was IgAN. Other diseases, such as postinfectious glomerulonephritis, diabetic nephropathy, hypertensive nephroangiosclerosis, chronic interstitial nephritis, and vasculitis (ANCA-associated and Behcet’s disease) have rarely been reported. ARN developed in patients taking warfarin or DOACs, but was also documented in one case of dual antiplatelet therapy [14]. Interestingly, almost half of all ARN cases published in recent years were related to DOACs, especially dabigatran. These data are consistent with the results of recent analyses extracted from the International Pharmacovigilance Registry, which show that the reported annual rate of renal adverse events is almost 10 times higher for DOACs (7725 cases in 15 years) than for antivitamin K drugs (2145 cases reported in 50 years). According to this database, dabigatran and rivaroxaban are the drugs associated with a higher proportion of kidney-related adverse events, being 4.6% and 3.5%, respectively [15]. In the set of clinical cases of ARN, the median age of patients treated with dabigatran and rivaroxaban was 78 years. Apart from older age, most of the patients had more preexisting risk factors previously associated with ARN, the most common being diabetes, hypertension, heart failure, and CKD [1,2,3,16,17]. Only two patients had presumed normal kidney function before the anticoagulant was introduced, while most patients had CKD stage 2 or 3. The lowest-reported eGFR in one patient at the start of dabigatran therapy was the same as in the patient presented in our case, that is, 35 mL/min/1.73 m2 [18].
The risk of developing the disease is undoubtedly much higher in over-anticoagulated patients, but ARN is not always related to excessive anticoagulation [1]. According to the data of our national cohort, two patients with histologically proven warfarin associated ARN had an INR that was even below the therapeutic range at the time of ARN diagnosis. Based on these observations and animal studies of ARN [19], it has been suggested that excessive anticoagulation alone is not sufficient. It is consequently now believed that for significant renal bleeding to develop, the glomeruli must be vulnerable to glomerular hemorrhage.
Based on the national and international data we have collected, the most common susceptibility to the disease appears to be due to a preexisting glomerulopathy, particularly IgAN. It appears that IgAN is exceptionally susceptible to anticoagulant-induced glomerular hemorrhage, but the reason for this remains poorly understood. In patients with IgAN, glomerular changes are characterized by hematuria caused by leakage of erythrocytes through the glomerular basement membrane into the urinary space, resulting in the formation of occlusive RBC casts in the tubules. As confirmed by our study, in contrast to the histological presentation of mild IgAN, much more numerous RBC casts are seen in patients with concomitant ARN. Namely, of 347 preimplantation kidney biopsies performed at our transplant centre over the past six years, we found IgA deposits consistent with IgAN (staining for IgA at IF ≥1+) in 50 (14.4%) preimplantation biopsies. These patients had mild IgAN, with only focal mesangial proliferation with an Oxford classification score comparable to the group of patients with ARN and underlying IgAN presented here (unpublished data). However, scarce RBC casts were detected in only 2 of 50 preimplantation biopsies with IgAN, whereas numerous RBC casts were present in all cases of ARN with underlying IgAN. Based on these data and supported by animal studies [19], we assume that more severe glomerular hemorrhage seen in patients with ARN, with extensive tubular obstruction by RBC casts, is not due to mild glomerular injury, but rather provoked by (usually) overt anticoagulation. After glomerular hemorrhage, further exacerbation of renal injury is associated with direct damage to tubular epithelial cells by oxidative stress, in which free hemoglobin binds to receptors in tubular cells and activates the formation of reactive oxygen species and an inflammatory response (16). The latter is consistent with the detailed findings of the pathohistological analysis of our patients, in whom the degree of renal injury appears to depend more on the extent of tubular damage, the number of occlusive RBC casts and accompanying interstitial edema than on the severity of the underlying glomerulopathy.
To detect ARN in patients receiving anticoagulants, we examined kidney biopsies from all patients treated with anticoagulant therapy or receiving anticoagulant prophylaxis before biopsy (Supplementary Materials). Histological reexamination revealed various renal diseases, but in none of these cases did we find a specific pattern of acute tubular injury and occlusive RBC casts characteristic of ARN, which could not be explained by concomitant glomerulonephritis. However, in biopsies with extensive glomerular changes, including endocapillary proliferation and crescents in ANCA vasculitis or immune complex glomerulonephritis, possible incidental signs of ARN may go undetected due to glomerulonephritis-related RBC casts and tubular injury, and these patients require thorough monitoring of kidney disease and anticoagulant therapy. According to the results of our study, ARN is histologically characterized by a specific pattern of acute tubular injury and occlusive RBC tubular casts combined with mild glomerular changes that are disproportionate to the glomerular injury. Indeed, other entities, including mild IgAN on preimplantation biopsies or kidney biopsy findings from patients on anticoagulant therapy, do not fulfill both features of kidney damage. However, it is important to emphasize that in the case of a suboptimal renal biopsy without medulla, where the majority of RBC casts were usually detected, only acute tubular injury may be detected and ARN overlooked. Although an experienced pathologist might suggest ARN, an accurate diagnosis still requires a thorough clinicopathologic correlation focusing on the patient’s medication, gross hematuria, and clinical course of kidney disease. Thus, a representative kidney biopsy specimen and accurate clinical data are therefore both indispensable factors to correctly diagnose ARN.
After supportive measures and reversal of anticoagulation, renal function and hematuria were restored in three patients (patients no. 3, 10, 13), with ARN presenting as mild renal insufficiency and associated histology showing mild acute tubular injury and interstitial edema. Supportive measures with temporary complete discontinuation of anticoagulant therapy, when possible, or at least strict optimization of anticoagulant therapy, is thus probably a sufficient step to enable a favorable outcome in mild clinico-pathologic forms of ARN. One patient with advanced glomerulosclerosis (with no prospect of improvement) was not further treated. This was the only patient who progressed to end-stage renal failure. One patient with a severe form of ARN and multiple comorbidities (patient no. 11) could not be treated with steroids due to contra-indications. His renal function improved only slightly after conservative measures (eGFR increased from 7 to 15 mL/min/1.73 m2). This patient left the hospital of his own free will, and was lost for follow-up. Importantly, anticoagulant therapy could not be discontinued in either of these two cases because of a mechanical aortic valve.
Among our ARN patients, 8 of 13 (61.5%) were treated with steroids. In the steroid-treated patients, renal function had improved markedly at the time of the last follow-up visit compared with the time of diagnosis. Because methylprednisolone was not introduced until after the renal histology report was obtained, the median time from admission to treatment was longer in patients treated with DOACs than in patients treated with coumarins (19 vs. 6.5 days), in whom more time was needed to meet the hemostatic criteria for performing a safe biopsy. In an overall view of the data obtained, the improvement in renal function seems to be slightly better in ARN patients treated with coumarins than those receiving DOACs (also taking into account the duration of follow-up). However, either a direct relationship between the duration of excessive anticoagulation and the severity and persistence of tubular injury, or a possible association of a more favorable outcome in the case of earlier introduction of methylprednisolone, was difficult to establish in our small, heterogenous group of patients.
Although early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [20,21,22,23,24], the use of corticosteroids in ARN is still limited to a few reported cases [25,26]. Our decision to treat with steroids was based on clinical judgement and the extent of pathohistological changes associated with acute tubular injury. Indeed, subsequent retrospective insight shows that, in our case series, steroids were used to treat those ARN patients who had a clinically severe, non-resolving form of acute kidney injury, reflected by an average 239% increase in serum creatinine and usually presenting with macrohematuria. Consistent with the clinical picture, these patients had histological signs of diffuse moderate or moderate/severe acute tubular injury in 70–100% of tubules, with extensive (40–100%) interstitial edema and a markedly higher number of obstructive RBC casts. At the same time, the glomerular tufts were without appreciable proliferative lesions.
Inevitably, we find it necessary to mention that in the current absence of clear recommendations for the treatment of ARN, the decision to introduce steroids into the therapeutic protocol was largely based on the positive historical experience of our center in IgAN patients with AKI and macroscopic hematuria. Indeed, in 2009, Kveder et al. [27] observed signs of acute tubular necrosis and foci of interstitial nephritis (especially near the areas with the most extensive erythrocyte or hemoglobin casts) in a group of patients with IgAN and associated macromaturia. Regardless of the pathogenesis of such findings in patients with IgAN (please note that at that time, we were not familiar with ARN and anticoagulant therapy was not addressed), it was at this time that we gained our first insights into the possible tubulotoxic and inflammatory effects of occlusive erythrocyte and hemoglobin casts and realized possible favorable outcomes following corticosteroid treatment. In subsequent years, the etiopathogenesis of RBC cast-associated tubular injury has been attributed to the deleterious local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, leading to damage to the lipoprotein components of tubular cell membranes and ultimately to apoptosis/necrosis of the tubular cells [9,10]. Similar oxidative stress-mediated damage may also occur in some other conditions, such as ischemia-reperfusion injury [28,29] or cholesterol atheroembolism [30], in which corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Nevertheless, the results of our ARN patients are favorable, since only one patient required maintenance dialysis (7.7%), whereas in a previous series of histologically verified ARN, a much larger proportion of patients with ARN (66.7%) did not recover renal function [3].
At this point, however, it is important to recall the introductory case of a patient with ARN in whom renal function improved after the introduction of a steroid, but the outcome was fatal due to subsequent infection. In order to gain full insight into the benefits and risks of steroids in the ARN population, a prospective controlled study is therefore needed.
6. Conclusions
Anticoagulant therapy together with pre-existing glomerular injury may lead to ARN. This may occur regardless of the type of anticoagulant used, and is not necessarily associated with excessive anticoagulation. ARN is nowadays more often associated with DOACs, especially dabigatran.
For gross hematuria with worsening kidney function in a patient on anticoagulant therapy, ARN is strongly suggested and should be managed promptly.
Treatment of ARN is mainly supportive and includes normalization of clotting times to a therapeutic range. The role of steroids is still debatable, but they have successfully been used for management in the majority of our reported cases. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Currently, the most reasonable therapeutic approach in ARN is prevention. In view of the increased risks in patients with CKD, especially IgAN, kidney function and urinalysis should be performed in all patients before the initiation of anticoagulant therapy, and closely monitored thereafter.
Acknowledgments
We would like to thank Živa Pipan Tkalec for performing photomicrographs.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/796/s1, Table S1: Classification of patients with histological signs of diffuse tubular injury according to the associated cause suggested by clinicopathological correlation, Table S2: International ARN cases published from 2009 to 2019 (source Pubmed), Table S3: International case series with kidney biopsy findings from 2009 to 2019 (source Pubmed).
Click here for additional data file.
Author Contributions
Conceptualization, T.B.M., N.K., Ž.V.-H.; methodology, N.K., M.F; formal analysis, T.B.M.; investigation, T.B.M., Ž.V.-H., N.K., M.F.; data curation, T.B.M., Ž.V.-H., N.K., M.F., A.A.-R.; Writing—Original draft preparation, T.B.M.; Writing—Review and editing, Ž.V.-H.; visualization, N.K., M.F.; supervision, A.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was approved by the National Medical Ethics Committee (protocol code 0120-625/2017/4; date of approval 12.12.2019).
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article and supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Level of dabigatran in the presented case during hospitalization.
Figure 2 Light microscopy kidney biopsy findings: (A) Signs of acute tubular injury, occlusive red blood cell casts in the tubules, and diffuse interstitial edema (hematoxylin and eosin stain; original magnification × 200). (B) Mild glomerular segmental mesangial proliferation—mild IgA nephropathy and signs of acute tubular injury (hematoxylin and eosin stain; original magnification × 200). (C) Hemosiderin intracytoplasmic deposition in tubular epithelial cells (confirmed by Perl’s stain, original magnification × 200). (D) Occlusive red blood cell (RBC) casts not containing Tamm Horsfall protein (arrow; original magnification × 400).
Figure 3 Proposed clinico-pathologic flow-chart to approach anticoagulant-related nephropathy. Abbreviations: ARN-anticoagulant related nephropathy, CKD-chronic kidney disease, AKI-acute kidney injury, DOACs-direct oral anticoagulants, IF-immunofluorescence, Ig-immunoglobulin, C3-complement component C3.
jcm-10-00796-t001_Table 1Table 1 Laboratory and ultrasonography findings in the presented patient on admission.
Laboratory Analysis
Sodium 119 mmol/L
Potassium 5.2 mmol/L
Urea 15.2 mmol/L
Creatinine 373 µmol/L
eGFR (CKD-EPI) 10 mL/min/1.73m2
pH 7.33
Sodium bicarbonate 18.3 mmol/L
Hemoglobin 78 g/L
Mean corpuscular volume 88.5
aPTT 141 s
TT >150 s
TT-dabigatran 650 µg/L
Urine analysis
Urine sediment
Leukocytes >100 per HPF
Bacteria 0
Red blood cells >100 per HPF
Casts Rare per HPF
Immunologic findings
ANCA, anti-GBM Ab, ANA All negative
Doppler ultrasound
Imaging result Normal-sized kidney with preserved parenchymal thickness, increased echogenicity and increased RI, no signs of obstruction
Abbreviations: eGRF (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; aPTT, activated partial thromboplastin time; INR, international normalized ratio; TT, thrombin time; TT-dabigatran, the level of dabigatran; HPF, high power field; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM Ab, anti-glomerular basement membrane antibody; ANA, anti-nuclear antibody; RI, resistance index.
jcm-10-00796-t002_Table 2Table 2 Clinical and demographic data in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Pt Age Sex AC SCr Baseline (µmol/L) SCr at Biopsy (µmol/L)/eGF (mL/min) Increase in Serum SCr from Basal Level (%) SCr at Discharge (µmol/L)/eGF (mL/min) SCr (µmol/L)/eGF (mL/min) at Time of Last Follow up/Follow up Time Time to ARN from Introduction of AC Symptoms at Biopsy INR/aPTT (s)/Dabigatran level (µg/L)/Anti-Xa-Rivaroxaban (µg/L) Relevant Comorbidities Treatment Outcome
1 77 f warfarin not known 448 (10) >25 285 (13) 127 (35)/17 months 20 months gross hematuria supra-therapeutic INR was never recorded mitral and aortic valve stenosis, post CVI, meningeoma, recent breast cancer discontinuation of warfarin, methyl-prednisolone 3 × 125 mg iv, followed by 0.5 mg/kg bw for 1 month, then taper down until discontinuation in six weeks improvement of kidney function, no rea-appearance of gross hematuria, later aceno-coumarol was introduced with no ARN
2 74 m warfarin 150 510 (9) 240 337 (16) 137 (43)/21 months 2 years gross hematuria INR 3.8 atrial fibrillation, aortic stenosis, congestive heart failure, Parkinson’s disease discontinuation of warfarin; methyl-prednisolone 0.5 mg/kg bw for 1 month, then taper down until discontinuation in 6 months improvement of kidney function, no hematuria
3 66 f warfarin 110 first episode 129 (37), second episode 160 (28) first episode 17, second episode 45.4 120 (39) 126 (37)/43 months 3 months gross hematuria INR 1.63 atrial fibrillation, Sjogren’s syndrome, fibromyalgia discontinuation of warfarin; on re-introducement gross hematuria re-appeared with an INR 3.6, after that event warfarin was stopped improvement of kidney function, persistent micro-hematuria
4 51 m warfarin 170–200 249 (24) 46.5 253 (23) 174 (36)/15 months 15 years gross hematuria INR 5.0 mitral valve replacement, atrial fibrillation, CVI, diabetes mellitus type 2, cystostoma due to urethral stenosis temporary discontinuation of warfarin, LMWH introduced; steroids 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months; strict control of anticoagulant therapy improvement of kidney function, hematuria persisted; recurrence of gross hematuria after reintroduction of warfarin (at INR 5.0), improvement after correction of INR
5 76 m warfarin 430 487 (9) 13.30 on dialysis on dialysis/12 months 10 years gross hematuria INR 4.4 mechanical aortic valve, severe atherosclerosis, arterial hypertension, diabetes mellitus type 2, HBV infection dialysis, better control of INR no improvement of kidney function
6 69 m dabigatran, 2 × 150 mg 88 194 (30) 120.5 181 (32) 164 (36)/6 months 2 months microscopic hematuria dabigatran level 293 µg/L atrial fibrillation, arterial hypertension, diabetes mellitus type 2, ethylic liver cirrhosis discontinuation of dabigatran, methyl-prednisolone, 0.6 mg/kg bw 14 days, then taper down until discontinuation in 3 months improvement of kidney function, persistent microhematuria
7 67 m rivaroxaban (previously on apixaban and dabigatran which caused GI bleeding) 75 442 (12) 489.3 386 (13) 82 (86)/12 months 2.5 months gross hematuria INR 1.24, aPTT 45.1 s atrial fibrillation, IgA vasculitis with skin involvement discontinuation of rivaroxaban, methyl-prednisolone, 3 × 250 mg iv, followed by 0.8 mg/kg bw 1 month, then taper down until discontinuation in 4 months improvement of kidney function
8 82 f rivaroxaban (previously on apixaban for 5 days which was stopped due to skin rash) 119 315 (12) 164.7 267 (15) 179 (22)/15 months 1 week gross hematuria INR 1.65, aPTT 41.4 s, antiXa- rivaroxaban 28 µg/L -performed 21 days after rivaroxaban discontinuation atrial fibrillation, arterial hypertension, ischemic heart disease discontinuation of rivaroxaban, methyl-prednisolone, three pulses 500 mg, followed by 0.7 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, no hematuria
9 82 f dabigatran, 2 × 110 mg 124 373 (10) 200.8 401 (9) transient improvement of SCr 201 µmol/L, however numerous further complications (please see case report for details) 18 days gross hematuria 650 µg/L atrial fibrillation, diabetes mellitus type 2, arterial hypertension discontinuation of dabigatran, methylprednisolone.4 mg/kg bw 1 month, then taper down until discontinuation in 3 months improvement of kidney function, later re-bleeding on warfarin, death due to sepsis
10 56 f acenocoumarol (skin rash on warfarin) 72 (82) 81 (70) 12.5 95 (53) 80 (71) 11 months microscopic hematuria 2.42 mechanical aortic valve, atrial fibrillation, systemic lupus, Sjogren’s syndrome, IgA vasculitis with isolated skin involvement, kidney stone better control of INR in the lower level of therapeutic range persistence of microscopic hematuria, stable kidney function
11 66 m gross hematuria appeared after 8 days of LMWH therapeuric dose -previously aceno-coumarol 149 (42) 669 (7) 349 350 (15) unknown, the patient refused further treatment 26 years aceno-coumarol, LMWH 8 days gross hematuria, epistaxis INR 1.36, anti-Xa LMWH 0.69 mechanical aortic valve, IgA vasculitis with predominant skin involvement, SCr 108 µmol/L and micro-hematuria treated with steroid prior to current hospitalization, infection of aortic stent graft, post CVI patient transiently converted to heparin; due to aortic stent graft infection steroid treatment was contraindicated gross hematuria resolved after LMWH was discontinued and patient was converted to heparin, kidney function slightly improved, acenocoumarol was reintroduced with no additionalbleeding episodes
12 60 m warfarin 74 372 (14) 402.7 274 (21) 206 (29)/1 month 3 months gross hematuria INR 3.46 arterial hypertension, portal vein thrombosis methyl-prednisolone i.v. pulses 3 × 500 mg, then 0.8 mg/kg bw for 1 month (still on therapy), anticoagulant stopped improvement of kidney function
13 81 m warfarin 13 years converted to dabigatran 3 weeks prior to biopsy 117 (53) 141 (40) 20.5 114 (52) 117 (50)/12 months 3 weeks post introduction of dabigatran gross hematuria INR 1.31, aPTT 78.1 s, dabigatran level 65 µg/L chronic heart failure, chronic Budd Chiarri, post cerebrovascular insult discontinuation of dabigatran improvement to baseline function in three weeks
Abbreviations: Pt, patient; AC, anticoagulant; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ARN, anticoagulant related nephropathy; INR, international normalized ratio; aPTT, activated partial thromboplastin time; CVI, cerebrovascular insult; HBV, hepatitis B virus; IgA, immunoglobulin A; LMWH, low molecular weight heparin.
jcm-10-00796-t003_Table 3Table 3 Histological findings in kidney biopsies in a Slovenian cohort of patients with anticoagulant-related nephropathy.
Patient No. Kidney Biopsy Oxford Classification EM–GBM Podocyte Effacement RBC Casts Global Glomerulo-Sclerosis ATI ATI Degree Interstitial Edema Interstitial Infiltrate Perls IFTA
1 ARN, IgAN M0, E0, S1, T0, C0 185–370 nm, average 280 nm no 5.70% 7/20 100% moderate 100% none tubuli ++ int. + 15%
2 ARN, IgAN M0, E0, S1, T0, C0 230–505 nm, average 350 nm no 9.30% 5/23 90% moderate/severe 90% 5% tubuli + int. + 15%
3 ARN, IgAN M0, E0, S1, T0, C0 230–385 nm, average 325 nm no 6.40% 0/6 50% mild 10% none tubuli ± int. − 10%
4 ARN, IgAN M0, E0, S1, T2, C0 220–400 nm, average 300 nm 30% 7.80% 4/29 70% mild 70% up to 10% tubuli ++ int. ± 20%
5 ARN, 50% global glomerular sclerosis, unclassified / 230–515 nm, average 370 nm no 3.20% 7/14 70% mild/moderate 40% none tubuli ± int. − 20%
6 ARN, thin GBM, latent IgA deposits M0, E0, S0, T0, C0 155–265 nm, average 190 nm 20% 7% 2/12 50% mild 25% up to 5% tubuli +/++ int. − 15%
7 ARN, IgAN M0, E0, S0, T0, C0 165–425 nm, average 285 nm 15% 10% 1/18 90% moderate 90% up to 10% tubuli + int. + up to 10%
8 ARN, IgAN M0, E0, S0, T1, C1 210–440 nm, average 325 nm not aplicable due to glomerular colapse 4.80% 3/17 50% mild 20% up to 10% tubuli ± int. + 10%
9 -case report ARN, IgAN M0, E0, S0, T0, C0 165–475 nm, average 320 nm not applicable due to glomerular collapse 8.10% 1/11 100% severe 100% 5% tubuli +++ int. ++ 10%
10 ARN, IgAN M0, E0, S0, T0, C0 120–305 nm, average 200 nm 20% 2% 1/10 25% mild 25% none tubuli ± int. − 10%
11 ARN, IgAN, benign nephrosclerosis M0, E0, S0, T0, C0 210–415 nm, average 290 nm 10% 20.30% 1/8 100% mild/moderate 40% none tubuli ± int. − up to 5%
12 ARN, IgAN M0, E0, S0, T0, C0 165–335 nm, average 260 nm 15% 4.90% 3/17 80% moderate 45% up to 10% tubuli + int. ± 5–10%
13 ARN, IgAN M0, E0, S0, T0, C0 225–400 nm, average 305 nm not applicable due to glomerular collapse 3,3% 2/22 20% mild 5% up to 10% not performed 20%
Abbreviations: EM–GMB, electron microscopy-glomerular basement membrane; RBC, red blood cell; ATI, acute tubular injury; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; ARN, anticoagulant related nephropathy; int., interstitium. | Fatal | ReactionOutcome | CC BY | 33669373 | 15,755,299 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy partial responder'. | Murine Typhus Infection in Pregnancy: Case Series and Literature Review.
Murine typhus is a flea-borne disease of worldwide distribution with a recent reemergence in the United States of America. There are limited data about the presentation, treatment, and outcomes in the pregnant population. We report on two cases of murine typhus during pregnancy and review the literature to compile previously reported cases. A comprehensive search was performed via the PubMed database for published articles between 1990 and 2020. Seven articles met the criteria of symptomatic pregnant murine typhus infection. A total of 37 patients were identified. Patients frequently presented with a prolonged duration of fevers prior to presentation, headache, and elevated hepatic transaminases. The diagnosis was predominantly based on serology. Treatment varied. Overall, the pregnancy outcome was favorable. Murine typhus can mimic other pregnancy-related pathologies. More exclusive and large-scale studies are needed to learn more of murine typhus during pregnancy.
1. Introduction
Murine typhus (MT) is a flea-borne disease caused by Rickettsia typhi [1]. MT has a worldwide distribution, but most reported infections arise from Southeast Asia, Northern Africa, Australia, China, and North America [2]. It is known to be prevalent in cities and ports where rats (Rattus spp.) and their fleas (Xenopsylla cheopis) thrive [3]. In the United States, the disease is endemic in Texas, Southern California, and Hawaii. In the past few years, there has been a reemergence of R. typhi infections in the United States (USA), likely due to shifts in the reservoir and vector [4,5]. Whereas the rat flea is the primary vector throughout the world, the cat flea (Ctenocephalides felis) is the contemporary vector in the USA [4,6]. Prior studies on the prevalence of R. typhi-infected fleas in cats have been contradictory, but even the low infection rates cannot exclude the role of cats in the transmission of the disease [7]. In Texas, R. typhi-infected cat fleas are carried mainly by opossums [4,7] (Figure 1).
Infection is thought to be acquired when flea feces contaminated with the bacteria are inoculated into a wound (such as the flea bite) or mucous membranes (Figure 1). Other potential mechanisms are inhalation of infected flea feces or direct inoculation via a flea bite. The incubation period of most rickettsial diseases varies between 5 and 14 days. Infection in the general population tends to be mild, with patients presenting with an undifferentiated febrile illness. Severe manifestations, such as acute kidney injury, respiratory insufficiency, delirium, coma, and death may occur. Diagnosis is empirical, and it is confirmed by serology (usually with the indirect immunofluorescence assay (IFA)) demonstrating a fourfold increase in IgG (Immunoglobulin G) titers between acute- and convalescent-phase specimens. Studies from spotted fever group rickettsioses have shown that IgM is not more sensitive than the IgG isoform. IgM (Immunoglobulin M) is also subjected to higher cross-reactivity, making IgG more attractive for the diagnosis [8]. One of the main challenges regarding laboratory diagnosis is that reactive antibodies are usually not present during early illness [4]. Therefore, prompt clinical diagnosis and empiric treatment are important, as early treatment has been associated with good outcomes [9]. Other less common forms of diagnosis are polymerase chain reaction (PCR) amplification of rickettsial DNA and immunohistochemical demonstration of R. typhi from tissues or cultivation of the organisms in cell culture. Their high costs and need for specialized equipment limit their widespread use [8].
There have been efforts to alert physicians to the disease in the general population, as diagnosis relies on clinical suspicion. However, little is known about the incidence, presentation, treatment, and overall outcomes of MT during pregnancy. We herein present two cases of murine typhus during pregnancy from Texas. Subsequently, we reviewed the literature on all reported cases of symptomatic murine typhus during pregnancy in the past 30 years and summarized the clinical findings.
2. Case Series
2.1. Case Reports
2.1.1. Case 1
A 36-year-old G7P4 30-weeks-pregnant patient, with a past medical history of prior pregnancies complicated by preeclampsia, and chronic headaches, presented with fevers and worsening headaches (HAs) of 1-day duration. The HAs were frontal, dull, without radiation, 8/10 in intensity, and partially improved with acetaminophen. She was from East Texas. The family history and medications were noncontributory. On admission, the temperature was 38.3 °C, blood pressure 104/76 mmHg, heart rate 116 beats per minute (bpm), respiratory rate 18 respirations per minute (rpm), and the oxygen saturation was 96% at room air. The physical exam was appropriate for gestational age. The laboratories were significant for leukocytosis (15,140 cells/mm3 with bands), relative thrombocytopenia (196,000 cells/mm3 from a baseline of 258,000 cell/mm3), and hyponatremia (serum Na 130 mml/L). Her blood cultures, influenza swab, and urine culture were negative. There were no abnormalities on the fetal parameters or fetal ultrasound. She was given supportive care. On hospital day (HD) 4, the patient developed worsening HA, fever (39.4 °C), and respiratory distress (saturation of 88–90% on 4 L of supplemental oxygen). Her blood work revealed worsening thrombocytopenia (138,000 cells/mm3) and an abnormal liver profile (alkaline phosphatase (ALK) 40 IU/L, alanine aminotransferase (ALT) 76 IU/L, and aspartate aminotransferase (AST) 100 IU/L). Computed tomography of the chest showed no pulmonary embolism but demonstrated diffuse septal thickening and patchy central ground-glass opacities with reactive lymphadenopathy. An echocardiogram was unremarkable. She was started empirically on furosemide for fluid overload and ceftriaxone plus azithromycin for community-acquired pneumonia on HD 6. A respiratory PCR panel was negative for common pathogens. On HD 9, the patient continued to be febrile. The Infectious Diseases Consultation Service recommended continuing with azithromycin and obtain serologies for murine typhus. Due to persistent headaches, a magnetic resonance imaging of the brain without contrast and a magnetic resonance venography were performed, showing no acute intracranial abnormality and no evidence of venous sinus thrombosis. A lumbar puncture was performed, and analysis of the cerebrospinal fluid (CSF) revealed pleocytosis (White Blood Cell count (WBC) 120 cells/μL, 44% neutrophils), hypoglycorrhachia (44 mg/dL), and an elevated protein level (81 mg/dL). The bacterial, fungal, and acid-fast bacilli cultures were negative. On HD 10, MT serology revealed an IgM titer of 1:1024 and an IgG titer of 1:512 (Rickettsia IFA IgM and IgG kit, Semi-Quantitative Indirect Fluorescent Antibody, Focus Diagnostics Inc., Cypress, CA, USA). The patient’s symptoms improved, and a course of azithromycin was completed. The subsequent serology, performed 27 days after the last serology, revealed an MT IgM titer of >1:1024 and an IgG titer of 1:256 compatible with probable but not definite, MT, as a fourfold change in titers could not be confirmed. She had no further complications during her pregnancy, delivering a healthy baby via cesarean section due to non-reassuring fetal heart tones at 39 weeks.
2.1.2. Case 2
A 20-year-old G1P0 patient at 12 weeks of gestation with poor prenatal care, presented with 7 days of fever, headaches, myalgias, and a maculopapular rash. She was from Southeast Texas, and she reported contact with a flea-infested stray kitten. She had no significant family or social history. She was not taking any medications. On admission, her temperature was 38.5 °C, heart rate 124 bpm, blood pressure 131/78 mmHg, respiratory rate 18 rpm, and the oxygen saturation was 97% at room air. The physical exam was relevant for mild bilateral cervical lymphadenopathy, right leg tenderness to palpation without edema, and a maculopapular rash on her upper extremities. The laboratories demonstrated hyponatremia (Na 128 mmol/L), hypokalemia (K 3.2 mmol/L), glucose 94 mg/dL, elevated transaminases (ALT 216, AST 152 IU/L), bandemia (WBC 7.86 cells/mm3 with bands), and thrombocytopenia (PLT 145,000 cells/mm3, baseline 216,000 cells/mm3). The serologies for parvovirus, toxoplasmosis, bartonellosis, CMV, HIV, syphilis, and viral hepatitis were non-reactive. The blood cultures were negative. The urinalysis revealed 17 WBC and mild proteinuria. An abdominal ultrasound showed a normal liver and gallbladder. A lower extremity ultrasound showed no deep venous thrombosis. The fetal ultrasound and hemodynamic parameters were within normal limits. A lumbar puncture was performed, and the laboratory studies of the CSF were unremarkable. On HD 4, the patient was empirically treated with doxycycline, and sera were tested for typhus group antibodies given high concerns for MT. Her fever, rash, and other symptoms resolved. The R. typhi IFA demonstrated an IgM titer of 1:512 and an IgG of 1:128 (Rickettsia IFA IgM and IgG kit, Semi-Quantitative Indirect Fluorescent Antibody, Focus Diagnostics Inc., Cypress, CA, USA). The convalescent serum obtained 15 days after, showed an IgM titer of 1:1024 and an IgG of 1:1024, confirming the diagnosis of murine typhus. She subsequently delivered a healthy baby at 39 weeks via cesarean section due to fetal intolerance to labor.
3. Materials and Methods
A PubMed search was performed using the terms “murine typhus” “pregnancy”, “endemic typhus”, “R. mooseri”, and “R. typhi”. The only articles considered were those based on human symptomatic infection during pregnancy, electronically available in English, and published between January 1990 and November 2020. Exclusion criteria were asymptomatic murine typhus in pregnancy (based only on seropositivity) and undiagnosed febrile illness in pregnancy. Data were extracted based on the number of patients, demographics, past medical history, presentation, diagnosis, treatment, and overall pregnancy outcome after infection. Poor outcome was defined as stillborn, prematurity (<35 weeks), and fetal growth restriction (birth weight < 10th percentile). Full term was defined as delivery between 37–42 gestational weeks. Maternal comorbidity was defined as the presence of diabetes, hypertension, asthma, thyroid disorder, obesity, mental health conditions, co-infection with another pathogen (e.g., malaria, dengue, and scrub typhus), and substance and/or tobacco abuse [10]. Fever was defined as T > 38 °C. Lastly, hyponatremia was defined as < 134 mEq/L, absolute thrombocytopenia as PLT < 150,000 cells/mm3, and transaminitis as ALT > 40 IU/L. Information from the aforementioned cases was included in the analysis. A literature review was later performed based on available published data.
4. Results
Result Data
Seven articles were found describing MT during pregnancy. Of those, five were case reports [11,12,13,14,15,16,17], and two were based on observational population studies [15,16].
Data from the reported cases are presented in Table 1. A total of 37 pregnant patients with fever due to murine typhus were identified. Overall, there was heterogeneity in gestational age during infection, with 7/22 patients presenting during the first trimester. The origins of the populations of these reports were diverse: Southeast Asia (n: 29), USA (n: 6), Australia (n: 1), and the Middle East (n: 1). The age ranged from 17 to 36 years. Maternal comorbidities were present mainly in the Asian studies, corresponding to smoking and co-infections with malaria, dengue, pyelonephritis, and scrub typhus. Only a few studies reported risk factors for infection (3/7).
All patients presented with fever (>38.5 °C), and the median for the duration of fever prior to admission/diagnosis was 7 days. They frequently presented with headache (21/22, 95%) and elevated liver enzymes (8/8, 100%). Diagnosis of MT was mainly based on serology, although some were positive by PCR. PCR results were exclusively reported from Asia, while cell-free next-generation sequencing was used twice in the USA.
Treatment for MT varied. The use of erythromycin or ampicillin was noticed in earlier reports, while azithromycin and doxycycline were seen in later reports. From the Asian reports, eight cases were not treated and had spontaneous resolution with good outcomes. With the exception of the studies originating from Southeast Asia, there were no poor pregnancy outcomes noted in the USA, Australia, or Cyprus [11,12,13,14]. In the study by McGready et al., three patients had a poor outcome: one stillborn, one born prematurely, and two with low birth weight. Five patients in this study had other comorbidities (e.g., malaria co-infection, and smoking history) [15]. In the study by Chansamouth et al., a total of 15 patients were found with MT by serology or PCR. Most of the patients had a relatively uncomplicated pregnancy, except for two cases that had preterm births and coincidentally did not receive any anti-rickettsial treatments [16].
5. Discussion and Literature Review
Arthropod-related infections are on the rise globally. From 2004 until 2016, the overall reported cases in the USA have tripled, with a total of 642,602 cases [18]. The national prevalence of MT is not accurately known due to variable reporting and underdiagnosis. In Texas, there have been 3507 cases reported from 2008 to 2018, while in California, 1185 cases were diagnosed between 2001 and 2020 [5,19]. The numbers are expected to be even higher in Southeast Asia. Accurate epidemiological data are lacking, but prevalence studies in the area range from 0–21.5% [20]. Geographical, socio-economic, vector distribution, and increased interest in the field are some of the reasons for these findings [20]. However, due to a lack of accurate point-of-care diagnostic methods as well as clinical recognition, they were often underreported. Studies investigating febrile illness during pregnancy differ on the main causal agent. In the Thai–Burmese population, the most common agent was malaria, compared to Laos, where dengue was more frequent [16,21]. However, nearly 5–10% of the patients had a co-infection with a rickettsial/rickettsial-like organism and up to 12% of patients had a rickettsial/rickettsial-like monoinfection [16,21,22]. In the past several years, there has been an increase in reports describing scrub typhus (an arthropod-borne disease caused by Orientia tsutsugamushi) during pregnancy associated with poor fetal outcomes [16,21,23]. Aside from a few observational studies, there are limited data regarding murine typhus during pregnancy. Unlike other tropical infections, such as leptospirosis and malaria, there are no data suggesting an increased incidence of MT in pregnancy [15,16].
In pregnancy, MT can mimic serious conditions that could impair the pregnancy if not addressed early. The differential diagnosis includes typical or atypical preeclampsia, given the presence of headache, thrombocytopenia, and abnormal liver function tests [6,21]. In up to 15% of patients, hemolysis, elevated liver enzymes, and low platelets syndrome (HELLP) can present without concomitant hypertension or proteinuria [14]. Chorioamnionitis and other infectious etiologies, such as those belonging to Toxoplasmosis, Others, Rubella, Cytomegalovirus, and Herpes viruses (TORCH) syndrome and arthropod-borne illnesses (e.g., scrub typhus, malaria, dengue, and Zika), could present similarly to MT. The disease should be high on the differential diagnosis when there is a history of exposure and knowledge of local epidemiology. Based on the data herein presented, MT does not seem to occur preferentially at any particular gestational age. Based on our findings, most patients present with a history of fever (>7 days) and remain hemodynamically stable. They present with headache, myalgias, arthralgia, which may be accompanied by a faint maculopapular rash. The most common abnormal labs are elevated liver enzymes and thrombocytopenia. The confirmatory diagnosis was mainly based on serology and PCR amplification of rickettsial DNA. Recently, the use of microbial cell-free DNA in human plasma has become an attractive option for the diagnosis of MT, given the potential of higher sensitivity than conventional molecular diagnostic tests such as PCR [17,24,25]. However, this novel modality is not widely available as a standard diagnostic test.
In regard to the pregnancy outcome after these infections, natural history appears to be benign. In one study on the Thai–Burmese border, 33% of patients (n: 4) had poor prenatal outcome [15]. It is known that in resource-limited tropical countries, arthropod-borne infections in pregnancy are associated with poor outcomes [15,22]. In regard to MT during pregnancy, the relationship is less clear. Some observational studies in Southeast Asia have associated MT with low birth weight and stillbirths; however, the small sample makes it difficult to prove an independent association [21]. The pathogenesis of possible worse outcomes in pregnancy during rickettsial infections, if any, is unknown. Studies have speculated that endothelial damage causes a circulatory impediment, likely due to thrombotic occlusion or coagulopathy [26]. On the other hand, animal studies have shown no passage of the bacteria via placenta or through breastfeeding even when high blood concentrations of bacteria were noticed [6,27]. Based on our analysis, poor outcomes with R. typhi infections were noted only in limited-resource countries, where other cofounders such as poor nutrition, lack of perinatal care, and co-infections are present. In our review, there did not appear to be any differences in pregnancy outcomes and stage of pregnancy when patients were infected.
In the general population, first-line therapy for all rickettsioses, including MT, is tetracyclines. The use of tetracyclines in pregnancy has been an area of debate. Prior studies associating discoloration of developing permanent teeth in children and hepatic failure in pregnant women were based on the use of older formulations (e.g., tetracycline hydrochloride, oxytetracycline) but not doxycycline. Older tetracyclines caused discoloration of the primary teeth when taken during the 4th–5th month of gestation [6]. Large-scale observational studies and systematic review of the literature shows no increase in the incidence of congenital malformations with doxycycline [28,29]. Furthermore, case-control studies have shown that there was no significant difference in congenital abnormalities between the 2nd and 3rd month of gestation (the organogenesis period) with the exception of two cases with neural tube defect [30]. Despite all these recent data, the federal drug administration considers doxycycline a category D drug. Based on a systematic review of published data, the authors concluded that therapeutic doses of doxycycline are unlikely to have teratogenic risk, but more data are needed to strengthen the evidence for firmer recommendations [31].
Although previously reported success with macrolides has made them an attractive alternative during pregnancy [15], a recent prospective randomized trial based on 216 non-pregnant patients showed that doxycycline was superior to azithromycin for uncomplicated MT. Azithromycin was inferior based on fever clearance time, the time-temperature area under the curve, and frequency of treatment failure [32].
Reports documenting the treatment of MT during pregnancy overwhelmingly use agents other than doxycycline. One study, analyzing data of patients with MT and scrub typhus, showed that azithromycin was the most frequently administered therapy (66% of cases), while ciprofloxacin and others with no anti-rickettsial activity (i.e., ceftriaxone, ertapenem, and piperacillin–tazobactam) were used to treat the remaining cases. Although unable to adjust data based on the severity of the disease, treatment delay, pregnancy stage, or recurrent illness, patients with shorter fever clearance time were higher in the azithromycin group as compared to other non-tetracycline antibiotics [15]. There was a trend toward less poor neonatal outcomes in those treated with azithromycin as compared to those not treated at all, although the difference was not statistically significant. There was also a higher proportion of normal neonatal outcomes in those treated as compared to those who were not. Chloramphenicol has also been used in rickettsial diseases, but it should be noted that the drug crosses the placenta and is excreted in milk. Side effects that preclude its use are aplastic anemia and “gray baby syndrome” in neonates.
Based on the data available, it is not possible to make a conclusion on the optimal treatment for MT in pregnancy. The data favor the safety of doxycycline during pregnancy, which is the first-line therapy for the disease in non-pregnant patients. There is no specific protocol for the prevention of murine typhus. Infection is thought to occur due to the inoculation of infected flea feces into wounds or mucous membranes. Therefore, avoidance of the vectors and their hosts is recommended [33]. Experts recommend controlling flea-infested pets and rat populations around residencies and businesses. There are numerous commercial products available for use on pets and around homes [34].
Passive immunization has been observed in the offspring of rats via colostrum or milk, regardless of the maternal antibody titer. However, the titers were usually undetectable by week 4 after birth [27]. Neonatal studies assessing the duration and protection of MT by maternal antibodies are lacking. There are currently no vaccines available to prevent MT, and prior efforts attempting to target other rickettsioses (e.g., Rocky Mountain spotted fever and louse-borne epidemic typhus) have been partially successful in animal models but inadequate for human use [1]. Vaccine development is imperative, as rickettsioses as a group have biological weapon potential given the aerosolized particle stability, high virulence, non-specific clinical diagnosis, inefficient diagnostic techniques, and low-level immunity [1].
The main limitation of this review is that the analyzed manuscripts were case reports and small prospective cohort studies; therefore, they are subject to recall and sampling bias as well as multiple confounding factors. Regarding our case reports, case #1 was defined as probable MT, not definite MT, as a fourfold change could not be observed. We were unable to test the specimens for PCR, as samples were not banked for a repository. Lastly, R. felis and R. typhi are sympatric and the possibility of some cases caused by R. felis instead of R. typhi is reasonable. However, prior studies in the Galveston area have shown a relatively low prevalence of R. felis in surveillance studies [4,7]. Furthermore, data from at least one person from Galveston during the disease’s local reemergence confirm that R typhi is circulating in humans [35].
Large-scale cohort studies exclusively studying MT during pregnancy are needed to fill gaps in knowledge regarding presentation, overall pregnancy outcome, and effectiveness of treatment during a particularly vulnerable state. This article provides an overview of MT presentation, diagnosis, and treatment in the pregnant population for the general clinician to consider, as it can mimic other pregnancy-related diseases requiring vastly different treatments.
6. Conclusions
Murine typhus in pregnancy is underreported. It can mimic other pregnancy-related pathologies. As noted in this literature review, confirmatory diagnosis is most often based on serology. The treatment varied, although doxycycline and azithromycin were the most frequently used. Overall, the pregnancy outcome seems to be favorable. More exclusive and large-scale studies are needed to learn more of murine typhus during pregnancy.
Author Contributions
All authors contributed to the manuscript; conceptualization—M.B.T. and L.S.B.; writing—M.B.T. and L.S.B.; review and editing—M.B.T., C.M.W., L.S.B., and M.L.R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Our institution does not require ethical approval for reporting individual or small case series.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study is contained within the article.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 “R. typhi transmission cycle.” R. typhi can be transmitted via different vectors depending on the geographic location. The R. typhi-infected rat fleas are involved in the transmission via rats. Infected cat fleas have been found in opossums and cats. Both of the vectors play a role in the transmission to humans. Infection reaches the human via infected flea feces inoculated in mucosa or wounds.
pathogens-10-00219-t001_Table 1 Table 1 Published case series about murine typhus in pregnancy (1992–2020).
STUDY INFORMATION
Author-Year Graves-1992 Koliou-2007 Gutierrez-2010 Jolley-2010 McGready-2010 Chansamouth-2016 Tanabe-2019 Stafford-2020
Location (Country) Australia Cyprus USA USA Thai-Burmanese border Laos USA USA
Number of patients 1 1 1 1 14 15 2 2
MATERNAL HEALTH
Age (mean/range) 17 30 26 33 27 (16–36) 28 (20–36) 29 (24–34)
Gestational Age (mean/range) 23 30 26 32 21 (7–39) 39 (35–40) 21 (12–30) 22 (13–31)
Maternal comorbidities (n) ** ✕ ✕ ✓ (5) ✓ (5) ✓ (1) ✕
Prior pregnancies (n) ✕ ✕ ✕ ✓ (11) ✓ (1) ✓ (1)
Risk factor for MT cats, opposums cats pets and fleas
CLINICAL COURSE
Headache (n) ✓ ✓ ✓ ✓ ✓ (13) ✓ (2) ✓ (2)
Rash (n) ✓ ✓ ✕ ✓ ✕ ✓ (1) ✓ (1)
Fever (n) ✓ ✓ ✓ ✓ ✓ ✓ (2) ✓ (2)
Transaminitis (n) ✓ ✓ ✓ ✓ ✓ (2) ✓ (2)
Hyponatremia (n) # ✕ ✕ ✓ ✓ (2) ✕
Thrombocytopenia (n) ✓ ✕ ✕ ✓ ✓ (2) ✓ (1)
Diagnosis serology serology serology serology serology, PCR serology, PCR serology microbial cell-free DNA
Treatment erythromycin erythromycin ampicillin azithromycin azithromycin azithromycin azithromycin, doxycycline azithromycin, doxycycline
FETUS HEALTH
Born at term (n) *** ✓ (1) ✓ (1) ✓ (1) ✓ (1) ✓ (10) ✓ (8) ✓ (2) ✓ (1)
Poor outcome (n) * ✕ ✕ ✕ ✕ ✓ (4) ✓ (2) ✕ ✕
REFERENCE 11 12 13 14 15 16 n/a 17
Footnote: ✓: present ✕: absent.* Poor outcome: stillborn, abortion, prematurity (<35 weeks), and fetal growth restriction (birth weight < 10th percentile). ** Comorbidities: diabetes mellitus, hypertension, substance abuse, tobacco use, co-infections, dyslipidemia, heart disease, eclampsia/preeclampsia. *** TERM: 37–42 weeks. # Hyponatremia < 134 meq/dL, Absolute thrombocytopenia PLT < 150,000 cells/cm3, Transaminitis ALT > ULN (40). (BLANK): Information not given. The table was filled based on the best information provided by the article. Totals do not equal 100% as some patients’ data were missing.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ACETAMINOPHEN, AZITHROMYCIN ANHYDROUS, CEFTRIAXONE, FUROSEMIDE | DrugsGivenReaction | CC BY | 33670581 | 19,364,152 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Osteonecrosis of jaw'. | Partial and Total Flap Failure after Fibula Free Flap in Head and Neck Reconstructive Surgery: Retrospective Analysis of 180 Flaps over 19 Years.
Fibula free flap (FFF) is widely used in head and neck reconstructive surgery and is considered as a standard and therapy of choice after ablative cancer surgery. The aim of this retrospective monocenter study was to determine the success rates of fibula free flaps for jaw reconstruction after ablative tumor surgery. The disease course of patients who underwent jaw reconstructive surgery with FFF from January 2002 to June 2020 was evaluated regarding the flap success rate. Flap failure was analyzed in detail and categorized into two groups: partial flap failure (PFF) and total flap failure (TFF). A total of 180 free fibular flaps were performed over the last 19 years and a total of 36 flap failures were recorded. TFF occurred in n = 20 (56.6%) and PFF in n = 16 cases (44.4%) cases. No statistically significant differences were found concerning patients' age at flap transfer, sex, BMI, ASA-Score, preoperative non-virtual or virtual surgical planning (non-VSP vs. VSP), and time of reconstruction (immediately vs. delayed). Duration of hospitalization shows statistically significant differences between both groups (p = 0.038), but no differences concerning operating time and duration on Intensive Care Unit (ICU). Partial flap failure appears to be underreported in literature. Sub- and complete failure of the skin paddle leads to clinical complaints like uncovered bone segments and plate exposure. Partial or complete FFF failure lead to infections on the recipient site and prolonged wound healing and therefore may cause a delay of the beginning of adjuvant radiation therapy (RT). PFF of hard tissue can be induced by RT.
1. Introduction
Since the first mandibular reconstruction with a fibula free flap (FFF) by Hidalgo in 1989, it has been shown that FFF is a reliable and versatile graft [1,2]. Currently, FFF is considered as standard therapy in head and neck reconstructive surgery, providing the optimal precondition for dental implant success and therefore for oral and dental rehabilitation [3,4]. Long-term complications on the donor-site are relatively low. Most patients have been satisfied with the functional and aesthetic results [5,6]. The number of free tissue transfers of soft and/or bone tissue defects have increased significantly in recent years [7]. The flap provides the opportunity to include a septo-cutaneous skin paddle of up to 200 cm2. Cadaver studies investigating skin perfusion through selective injection have shown that a skin area of 12 × 7 cm can be perfused by a single perforating vessel [8]. A recent milestone in operative techniques is the possibility of computer-assisted surgery (CAS) and virtual surgical planning (VSP) in reconstructions of jaws [9,10,11]. VSP initially focused on bone grafts. The innovative potential lies in the design of a cutting guide that takes into account the course of the cutaneous perforating vessels based on preoperative CT and sonographic measurements [12,13]. For skin paddle harvesting, the support of perforator vessels is crucial. Fibular flaps have been reported to allow a success rate of up to 95% [7,14,15,16]. The causes of flap failure are anastomosis insufficiency, more frequent venous congestion (e.g., edema, hematoma), rare arterial occlusion (e.g., embolism, thrombus, kinking), vasospasms, postoperative bleeding, and coagulopathies [17,18,19,20].
However, detailed data about partial FFF loss are rare and seem to be underreported in literature. An analysis of risk factors for flap failure and complications in a low-level center of 129 FFFs over a time span of 20 years reported a PFF rate of 7.8%. By definition, (sub-)total flap loss describes the failure of the skin paddle and/or the loss of one or more bone graft segments in poly-segmental reconstructions [21]. The data published to date lack a differentiation concerning soft and/or hard tissue loss. A comparative investigation on computer-assisted versus conventional FFF technique for craniofacial reconstruction found six skin paddle and two segmental graft failures, which corresponded to a PFF rate of 11.76% (n = 8 out of 68) and a TFF rate of 4.41% (n = 3) [22]. Comparative results of partial loss were reported with a range of 3–14% [16,23]. This should be considered when the often-described advantage of the skin paddle as a vital monitor is advocated [24,25]. Gennaro et al. mentioned that a thin muscle cuff around bone, e.g., the fibula or vascularized iliac crest bone flap, is needed for flap harvesting. In these cases, a direct clinical assessment even without the use of a Doppler probe is advisable [26]. However, if PFF or TFF occurs, therapeutic options and decisions must be made to reduce local infection, functional impairment, and increase the patient’s quality of life. In this study, we have assessed and discussed the therapeutic options in the setting of TFF.
The aims of this study are:to estimate the rate of partial flap loss ((sub-)total loss of skin paddle and/or failure of graft segments) and total flap failure over a long time period of 19 years, and to suggest further therapy procedures according to localization and defect type;
to examine a correlation between age at flap transfer, BMI, ASA-Score, and risk factors in terms of partial and total flap failure; and
to investigate whether there is a correlation between non-VSP vs. VSP and time of reconstruction (immediate vs. delayed).
2. Materials and Methods
2.1. Study Design and Patient Population
The study was conducted as a monocentric, retrospective study. Medical records of all patients who underwent FFF in the head and neck region from January 2002 to June 2020 were analyzed in respect of success of the flap transfer procedure. Flap failure was stratified into two groups: partial flap failure (PFF) and total flap failure (TFF) (Figure 1). PFF was defined as any loss of parts of the skin paddle (Skin) (Figure 2), parts or segments (poly-segmental reconstruction) of bone grafts (Bone) (Figure 3), or a combination of both (Both). The major characteristic of PFF is the remaining blood supply by the vascular pedicle. In contrast to PFF, TFF is characterized by discontinued perfusion of the graft (i.e., thrombosis). Intra- or extraoral wound dehiscences around the skin paddle alone did not match the criteria for PFF and were not included.
All patients underwent a preoperative CT or MRI angiography to ensure the presence of a three fibular vessel anatomy and the absence of significant arteriosclerotic changes in the lower leg. Free fibula flap dissection was performed by Gilbert’s lateral approach [27]. To preserve knee and ankle stability, respectively, a bone length of 8 cm proximal to the harvest site and a distal bone length of 6–8 cm of distal to the harvest site were left in situ. When an osseo-cutaneous free flap was harvested, a muscle cuff with parts of soleus and flexor hallucis longus muscle was included to protect the perforators. Before donor-site wounds were closed, a vacuum drainage (Redon) was installed. Wound closure at the lower limb was performed using a split skin graft over the harvested skin flap or primarily in all cases of sole bone flaps without skin paddles.
Examples for the clinical course of a subtotal bone graft loss (PFF) were illustrated in Figure 3, Figure 4 and Figure 5 and an example of TFF is demonstrated in Figure 6.
2.2. Study Parameters and Evaluator Calibration
The following parameters were collected: Patient age at the time of flap transfer, sex, primary diagnosis, planning procedure, location, type of defect classified according to Brown et al. [29,30], number of fibula segments, reconstruction time (immediately vs. delayed), flap condition, part of flap loss, and reason for flap loss. Patients’ medical records were analyzed independently for flap outcomes.
2.3. Inclusion and Exclusion Criteria for Study Subjects
In this study, we enrolled all patients who underwent a reconstruction of the maxilla or mandible (immediately or delayed) with a FFF. Only cases with incomplete data sets and/or medical records were excluded (n = 2).
2.4. Statistical Analyses
Fischer test and Freeman–Halton extension [31] were used to compare flap outcome with sex, ASA-Score, alcohol and tobacco abuse, time and method of reconstruction, and the number of fibular bone segments. Students t-test was performed to compare the mean age at FFF-transfer, operating time, duration in the ICU, and time of hospitalization between the three flap outcome groups after verification of normality. p < 0.05 was defined as statistically significant. The statistical analysis was carried out with SPSS 25 (SPSS Inc., Chicago, IL, USA).
2.5. Ethics Statement/Confirmation of Patients’ Permission
The study was approved by the local Ethics Committee of the Justus-Liebig University Giessen (AZ35/20) and patients’ consent was not necessary for this retrospective study. The patients consented that their intraoral pictures and X-ray images may be used anonymously in the publication. All data in the Microsoft Excel spreadsheet were pseudonymized.
3. Results
A total of 180 fibula free flaps (FFF) were performed over a period from January 2002 to June 2020. Complete flap success was recorded in 144 cases (80.0%). The remaining 36 flap failures were categorized into the two major groups partial (PFF) and total flap failure (TFF). PFF occurred in n = 16 (44.4%) and TFF in n = 20 (56.6%) cases (Table 1). No statistically significant difference concerning the age at flap transfer, sex, time, and method of reconstruction was apparent. Furthermore, no significant differences were detected in relation to surgical parameters (neck dissection, tracheostomy, radiation therapy) and general risk factors (alcohol and tobacco abuse). There is a significant difference concerning the duration of hospitalization between the groups PFF (mean 22.6 ± 9.7 days) and TFF (mean 33.8 ± 18.8 days) (p = 0.038). No statistically significant differences concerning operating time and duration in the ICU between PFF and TFF were detected.
While TFF occurred in a median 8.5 days, PFF was clinically incident later. All TFF were an early complication. Out of 20 TFF (100%), four arterial and four venous thrombosis were found during anastomosis revision. The aetiology of the flap failure of the remaining 12 cases (60%) are unknown. PFF of the skin paddle (n = 11) was observed in a median time of 22.5 days and therefore considered as a late complication. The onset of PFF of bone segments without skin paddles (n = 4) was detected much later at a median time of 101.5 days.
PFF was analyzed in detail. After maxillary reconstruction, two partial and three total flap failures were found in the investigation. This corresponds to 13.5% (n = 5) of the study collective. Two cases of PFF of the skin paddle was found after maxilla reconstructions (Brown Class II and III) with uni-segmental fibular, and three TFF were observed in uni- (n = 2) and bi-segmental reconstruction (n = 1).
In mandible reconstruction, PFF was observed in 87.5% of cases. A total number of 14 partial flap failures—nine losses of the skin paddle, four isolated bone graft losses, and one combination of both—were found in mandible reconstructions after tumor recurrence (Table 2). Out of 11 skin paddle losses (PFF), 81.81% (n = 9) occurred in the conventional non-VSP group.
TFF was observed mostly in Brown class I (n = 7) and II (n = 6) defects. Subtotal loss of the skin paddle was incident in 68.7% of cases (n = 11 out of 16). Isolated loss of fibular bone segments was found in 25.0% (n = 4) and a combination of both was reported in only one case (6.3%). PFF was found in 50.0% (8 out of 16 cases) of uni-segmental, 25.0% (n = 4) of bi-segmental, and 25.0% (n = 4) of tri-segmental jaw reconstructions. A total flap loss occurred in 55.0% of cases after bi-segmental and in 40.0% of cases after uni-segmental reconstructions (Figure 7). There was a non-significant trend towards TFF in poly-segmental reconstructions (p = 0.114).
A total loss of the skin paddle (n = 11) was observed at a mean of 27 days (median 22 days, range 2–67 days) and an isolated loss of bone graft segments at 181 days (n = 4; median: 101.5 days, range 37–499 days) post surgery. Kaplan–Meier survival function was calculated and visualizes the different periods of partial soft and hard tissue failure (Figure 8).
In comparison to the beginning of radiation therapy in the complete success group (n = 40, mean 52.9 days, median 49 days, range 21–98 days), PFF of the skin paddle generates a delay (Figure 9). Radiation therapy started at a mean of 63.5 days (n = 4, median 50.5 days, range 39–114 days). The difference remains without any statistical significance (p = 0.358).
Clinical flap necrosis and time of bone graft removal were compared with the number of bone segments used. Statistical analysis showed no significant differences between the uni- and bi-segmental graft losses. Overall, clinical flap loss was observed at a mean of 12 days after surgery (Median 8.5 days, range 0–40 days) and surgical removal of the avital grafts at a mean of 86.4 postoperative days (Median 22.5 days, range 2–503 days) (Figure 10).
Comparing TFF after maxillary and mandibular reconstruction, it is noticeable that maxillary TFF cases were a mean of 73.3 years old, and thus older than mandibular TFF cases (62.5 years). Therefore, with unequal variance, there is a statistically highly significant difference, which can be explained by the composition of the collective (p < 0.001). Regarding the first clinical sign of impending TFF, signs of TFF were documented after 3.3 days in the upper jaw and after 14.4 days in the lower jaw (Table 3). This observation is statistically significant (p = 0.007). Concerning further surgical procedure and removal of the necrotic graft, no statistically significant difference between maxilla and mandible was observed (Figure 11).
4. Discussion
4.1. Rate of PFF and TFF
Thrombosis, kinking, and spasm of the vessels have been reported as common causes of total free-flap failure in the early phase after microvascular anastomosis [32]. Venous thrombosis is more common than arterial thrombosis due to the low-flow and low-pressure venous system. Unrecognized venous thrombosis can lead to backward perfusion failure up to total stasis in the arterial system. This is followed by flap ischemia, no-reflow, and subsequent flap loss [33,34]. Fibular flaps are reported with success rates of up to 95.0% [7,14,15,16]. Study findings have shown a cumulative success rate of 88.9% (80.0% complete success and 8.9% partial flap failure). The total failure rate in the presented study is 11.1% over the last 19 years and over all types of indications for reconstruction, time of reconstruction, and method of planning (Non-VSP vs. VSP). In comparison to the here reported investigations, other reconstructive centers report total fibular flap failure rates of up to 12.4% (Table 4). Comparability of the results must be ensured concerning the chosen definition of flap success and PFF/TFF. In the presented study, strict criteria for PFF and TFF was defined. Only clear definitions will engage the collection of comparable data. Retrospective study design without standardization is often of poor data quality due to incomplete follow up data and different investigators. However, data collection over 19 years by a single investigator appears to be impractical. Loss and removal of the whole graft are clear parameters for TFF. From the clinical course and as a result of perfusion disorder through its vascular pedicle, TFF is an early flap failure. Therefore, minor, insufficient perfusion of flap elements leads to malnutrition, and thus to consecutive (sub-)total loss of skin paddle and/or bone segments. This was defined as PFF. PFF therefore does include the functional use of the flap and appears as a late flap failure. Most published data lack a differentiation between soft and hard tissue loss. Partial flap failure was reported with an incidence of 3–14% but has not been further differentiated in most cases (Table 4).
A retrospective single-center study on 129 FFF transfers over the last 20 years found TFF in 12.4% and PFF in 7.8% of cases [21]. An investigation on 20 virtual planned FFF showed that preoperative planning based on preoperative CT-scan allows to include the preoperatively planned skin paddle area [13]. Another clinical trial included preoperatively marked perforator vessels for skin paddle in digital planning and noted a survival rate of 92% (n = 24) in FFF transfer with three total and two partial skin paddle losses [12]. Other investigators observed seven total flap losses and three losses of skin paddle in a total of 99 FFFs [16].
In the present study, there were four losses of fibular bone segments and only two of them occurred after radiation therapy (RT). Loss of the skin paddle occurred in two cases of maxillary reconstruction and in nine cases of uni- and poly-segmental reconstruction of the mandible. After an average time of 27 days (median: 22 days, range 2–67 days), partial loss of the skin paddle was observed whereas partial bone loss occurred after mean 181 days (Median: 101.5 days, range 37–499 days). Swelling and edema are results of ongoing inflammatory processes and wound healing immediately after surgery. A critically reduced perfusion of the septo-cutaneous perforators could be the consequence. Its maximum dimension can be expected 2–3 days after surgery. The unusually late appearance of visible (sub-)total dysfunction of the skin paddle perfusion after more than the median time of 3 weeks should be interpreted with caution and as result of documentation bias. Any influence of RT in this respect can be excluded, since RT always started after PFF was already observed. The onset of adjuvant RT in the group PFF skin was at median 50.5 days (range 39–114 days) after surgery in comparison to the control group comprising complete flap success (n = 40), in which RT began in median 49 days (range 21–98 days) after surgery. A statistically significant difference could not be observed. However, an adjuvant RT for oncologic reasons was not to be delayed by a PFF. The results must be interpreted with caution due to the small number of cases. In the literature, the effect of prior irradiation on partial or complete loss of FFF compared with unirradiated grafts has often been reported to be statistically insignificant [38,39,40,41,42]. The effect of postoperative irradiation on partial flap failure in microvascular head and neck reconstruction has not been well described in literature and indicates that further studies are needed in this area. Verhelst et al. focused on perioperative irradiation but it was not identified as a statistically insignificant risk factor for flap failure [21]. In a study by He et al., 9 of 17 patients were irradiated postoperatively and all grafts sustained [43]. In this study, no cases of PFF were detected during or after RF. Under RT conditions, PFF could be similar to radiogenic oral mucositis, which is associated with an early inflammatory response [44,45]. These factors provide a target for biology-based mucositis-prevention strategies [46,47], and thus for PFF prevention. Further, the option of an additional skin paddle for defect closure after oncologic resection is without doubt one of the major advantages of the FFF in addition to its clinical and technical function of flap monitoring. On the other site, wound healing disorder of the donor site after skin paddle harvesting appears at a rate of 1.07–31.2% [23,48,49]. In literature, different techniques for closure of the donor site have been described [50]. Focused only on monitor function, the price for an unreliable monitor skin paddle seems to be high and should be critically reflected. Nevertheless, some authors believe that the reliability of the skin paddle for the closure of recipient site defects is insufficient in non-irradiated [51] and especially in irradiated patients [52]. In a retrospective investigation, Thome et al. observed 20% of skin paddle failures (n = 27) and came to a similar conclusion [53]. Other authors found a stable and sufficient vascular supply of the septo-cutaneous skin paddle by the septum intermusculare posterius and perforator vessels around the musculus soleus [54,55,56]. They emphasize the necessity of a muscle cuff around the posterior septum, which contains vessels that are crucial for skin paddle survival [24].
Partial bone loss may occur more frequently than previously observed and described in the literature as a result of malnutrition. Sufficient neovascularization to allow free-flap survival independent of the vascular pedicle has been reported to occur within 7 to 10 days in myo-cutaneous flaps [57,58,59]. In contrast, a comparative prospective clinical study measured hemoglobin oxygenation and capillary flow in 50 flaps (25 forearm flaps, 15 osseo-cutaneous fibular flaps, and 10 anterolateral thigh flaps) at 4 and 12 postoperative weeks. The authors found that flap autonomization rates were significantly higher in the lower jaw and non-irradiated defect sites. In addition, fascio-cutaneous flaps were found to be autonomized faster than osseo-myo-cutaneous free flaps. Myo-cutaneous flaps were never found to be autonomized after 4 weeks [60]. Kumar et al. studied blood supply of fascio-septo-cutaneous free flaps several months after surgery and found no significant blood flow through vessels across the flap inset [59]. Mücke et al. found that osseo-myo-cutaneous free flaps are significantly dependent on vascularity of the original anastomoses even 1 year after surgery [60]. According to their data, our findings should be interpreted as an adverse effect of radiation therapy (n = 2) and two “real” partial bone segment failures. The risk to develop osteoradionecrosis is decreased in patients with high body mass indices and on steroid therapy [61] through adequate soft-tissue bulk paired with the high-quality vascularized fibula bone [62]. Data published in the literature show that osteoradionecrosis of the original mandible occurred after a median time of 10.9 months (range 1.8–89.7 months) after RT and 90% occurred within 37.4 months [63]. In contrast, our data show bone loss after a median time of 3.38 months (range 1.23–16.63 months) and more than 6 months earlier. This observation should be interpreted with caution due to the low number of cases and should be further studied in larger study groups.
Early TFF was incident in n = 3 maxillary and n = 17 mandible reconstructions. TFF was found after mandible reconstruction in anterior defects (Classes III-IV, 3 out of 17 cases, 17.6%) and more frequently in lateral defects (Classes I–II, n = 14, 82.4%). Uni- and bi-segmental were commonly used for these Classes I–II reconstructions. Reasons for increased TFF in class I and II were critical pedicle course (inner surface of mandible and mouth floor), kinking of the vascular bundle [64] and length [21,65,66]. In addition to known general risk and complicating factors, further risk factors for flap failure include postoperative swelling and edema, hematoma, movement of the neck, circular tracheal tube fixation loop, and course of the vessel through the neck [33].
The therapeutic procedure for partial skin or isolated bone loss depends on the jaw affected. If PFF of the skin paddle occurs in the maxilla, it is usually an uncritical situation and wound healing from peri-osseous tissue can be expected. When bone loss in the maxilla occurs, a “simple” prosthetic rehabilitation by obturator prosthetic is a therapeutic alternative [67,68] if another microvascular bone graft is not desired. Large defects can be downsized with local tissue advancement. Functional impairment (eg. scars) might be addressed in a two-staged procedure. Safe flaps routinely used in our department are the temporal myo-fascial [69], pectoralis major [70,71], and deltopectoral flaps [72].
In the mandible, skin paddle loss is often noncritical when the primary bone graft is vital. After wound healing local flaps and staged scars, loosing procedures can be necessary to improve dysfunction such as trismus [73]. Flaps of choice in this situation are often radial forearm [74], pectoralis major [70,71], and deltopectoral flaps [72]. When PFF of bone segments or TFF after mandible reconstructions appear, there are different strategies available that need to be evaluated in light of the patient’s condition. If patient’s condition is poor and the avital graft showed no signs of inflammation, it was left in the oral cavity (Figure 6). If inflammation and/or loosening of osteosynthesis material occurred around the avital segment, removal is necessary. Sometimes further use of osteosynthesis is possible, especially if patient-specific osteosynthesis was used. However, in the majority of cases, removal of the osteosynthesis will become necessary (Table 3). Re-osteosyntheses could be useful in combination with distant flaps like pectoralis major flaps, deltopectoral flaps, and bone hip grafts. The staged procedure of second attempts microvascular bone graft is possible after critical evaluation. The removal of the avital graft and the anticipation of stable scars building and “functional” pseudarthrosis is a further option (Figure 6).
4.2. Influence of Age at Flap Transfer, BMI, ASA-Score and Risk Factors in Terms of Flap Success in Relation to PFF and TFF
In this study, no significant differences between patients’ age at flap transfer and flap outcome were observed. This confirms other investigations that patients’ age at flap transfer is not crucial for flap success [75,76]. It is a surrogate parameter for the general condition of the patient [77,78]. A prospective study on 215 patients found that age ≥ 70 years had a significantly higher ASA-Score and shorter duration of surgery. Age was a risk factor for longer ICU stay and complication rate. They found no influence of age on the length of hospital stay and overall success of microvascular reconstructions [79]. In this study, more than 92% were rated ASA 2 or 3. All partial flap failures and all but one total flap occurred in both groups. ASA score and duration of the operation were found to be independent risk factors for operative revisions [76]. In literature, ASA-Rating is correlated with a higher number of postoperative complications after microvascular reconstructions [80,81] and the overall survival [82]. We calculated the relation between ‘Age at flap transfer’ and BMI and found an evenly distributed pattern.
Concerning alcohol and tobacco abuse in the investigated group, no statistically significant differences were found. In published literature, alcohol abuse was identified as a risk factor for postoperative adverse events [82]. Tobacco abuse was shown to reduce overall survival time compared with non- and never-smokers [83,84]. A review by Van Imhoff et al. stated that survival rates are lower and recurrence rates are higher in patients who continued to smoke after having being diagnosed with Head and Neck SCC in comparison to patients who stopped smoking [85].
BMI had no statistically significant influence on flap success in this study. Low BMI or underweight at diagnosis was an independent, unfavorable prognostic factor [86,87]. Obesity was associated with better outcome and was not an independent risk factor for postoperative complications of free tissue transfer [88,89]. Other investigators found that higher BMI/obesity is a risk factor for peri- and postoperative medical complications [90].
The duration of hospitalization was calculated with a mean of 22.6 days in the PFF group and a mean of 33.8 days in the TFF group. Statistically significant differences (p = 0.038) were found in the occurrence of partial or total flap failures (Table 1). While the majority (68.75%, n= 11 out of 16) of all partial flap failures are a dysfunction of the skin paddle failures (mean duration of hospitalization partial flap loss group 20.71 days), we conclude that loss of that skin loss does not result in significantly longer hospital stay than in total flap losses. Stepwise removing of avital flap parts, deperiostizing of the bone graft, and covering with oral mucosa is an attempt for flap salvage. However, the initial stay at the ICU seems to have no statistical influence concerning upcoming PFF or TFF. It was calculated in both groups with a mean of approximately 2.0 days.
No statistically significant difference concerning mean operating time (PFF: meantime 546 min, TFF: meantime 524 min) and flap outcome was found. Surgery time is described as a risk factor for postoperative complications [91,92,93]. Increased operating time may also be the result of a younger surgeon learning and being taught by an older instructing surgeon. However, operating time should be reduced whenever possible [92]. The study could not include ischemia time in the risk analysis because this parameter was not recorded or was incomplete.
4.3. PFF and TFF in Non-VSP vs. VSP and Reconstruction Methods (Immediate vs. Delayed)
The majority of isolated skin paddle losses occurred in the non-VSP group. Reasons can be seen in mechanical trauma and manipulation during free-hand transplant forming i.e., preparation of bone segments and revised application of osteosynthesis. Individually custom-made cutting guides stabilize and preserve intersegmental connectors for stabilization of several bone segments, which provide a valuable support on the vascular pedicle during transplant preparation and shaping.
No statistically significant differences were found concerning patients’ preoperative planning procedure (non-VSP vs. VSP) and time of reconstruction (immediately vs. delayed). The results confirmed the findings of other clinical investigations [94]. A retrospective study of 128 osseous free flaps with a minimum follow-up of 12 months evaluated plate-related complications in patient-specific versus conventional fixation systems. They found more complications with patient-specific plates (e.g., wound healing disorders, plate exposure, fixation failure, and subtotal osseous union) in comparison to conventional reconstruction plates, but the differences were statistically insignificant.
One possible reason for (sub-)total bone loss despite maintained perfusion of the vascular pedicle might be trauma during preparation, segmentation, and shaping of the fibula graft. Preoperatively planned and fabricated saw guides and patient-specific implants ease and accelerate the surgical procedure itself, which should be helpful in avoiding mistakes and facilitating the handling of the fibula graft. More complex shaping and osteotomization of bone segments leads to manipulation of the vascular pedicle during dissection and puts it at risk [22]. Furthermore, the impact of VSP and patient-specific plates in terms of wound healing abnormalities, plate exposure, and subtotal osseous union shows a trend towards increased complication rates compared with non-VSP with hand-bended plates. Plate-related complications were increased with radiotherapy and multi-segment flaps [95].
Further investigations on partial flap loss of osseomyocutaneous FFF are needed.
5. Conclusions
The fibula free flap constitutes a standard therapy for jaw reconstructive surgery. The present results of 180 fibula free flap over a period of 19 years shows a cumulative success rate of 88.9%, which is well comparable with other studies. The findings of our long term monocenter retrospective investigation are a position statement about flap success and partial and total loss rates, which was achieved by careful patient selection and a two team approach to reduce operating time. In partial or total flap failure, no statistically significant correlation was observed between patient age, sex, ASA, BMI, alcohol and tobacco abuse, time, and method of reconstruction (virtual versus non-virtual surgical planning). Total flap failure caused significantly prolonged hospitalization time. Partial flap failure affected mainly the skin paddle. Two-thirds of these cases were found in the non-VSP group and only two cases were observed in the virtual surgical planning group. This could be attributed to protective effects of the cutting-guide template, which possibly decrease the mechanical trauma during surgery.
Acknowledgments
The authors are grateful for the consent of the patient for presented X-rays and clinical images. This publication is part of the second author’s dental doctoral thesis (SS).
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Author Contributions
Conceptualization, M.K.; methodology, S.S., M.K., C.B.; formal analysis, M.K.; investigation, M.K., and S.S; data curation, M.K. and S.S.; writing—original draft preparation, M.K., S.S., S.A. and S.B.; writing—review and editing, M.K., S.S., S.A., C.B., D.S., H.-P.H. and S.B.; visualization, M.K., D.S., H.-P.H. and S.A.; supervision, M.K., H.-P.H., S.B. and S.A.; project administration, M.K. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Justus-Liebig University Giessen (AZ35/20, approval 25.5.2020).
Informed Consent Statement
Patient consent was waived as the study is a retrospective data analysis.
Data Availability Statement
The data presented in this study are available upon request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Schematic illustration of reconstructive workflow and stratification in partial and total flap failure groups. The major characteristic of PFF is the remaining blood supply by the vascular pedicle. In contrast to this, TFF is characterized by interrupted graft perfusion.
Figure 2 Example of ‘PFF skin’ after maxilla reconstruction.
Figure 3 The clinical course of PFF. (OPT 1) Due to the recurrence of an ossifying fibroma (odontogenic tumor) in the ramus ascendens mandibulae in a 22-year-old patient, (OPT 2) a continuity resection and simultaneous reconstruction with a bi-segmental fibula and CAD/CAM plate was planned. (OPT 3) The clinical submandibular fistula had a connection to the plate (Figure 4A). (OPT 4) An OPT image was obtained after removal of the avital fibular segments and re-stabilization of the remaining graft. There is initial evidence of incipient bone healing on the proximal resection-site. (OPT 5) Follow-up visit at 9 weeks after re-stabilization. In the condylar segment, bone healing is pictured, and at the distal segment, progressive resorption is visible. (OPT 6) Progressive bone healing and callus formation originating from the resection site is visible 19 weeks after re-stabilization.
Figure 4 (A) Clinical aspect 4 weeks after reconstruction. After reopening the submandibular approach and excision of the skin fistula, there was no evidence of screw loosening. Temporary unscrewing of the screw (No. 5) leads to bleeding. (B) With a new fistula, the site was reentered 8 weeks after surgery and the screw was removed again. There was no clear bleeding from the screw hole. In addition, the anterior-caudal edge of the bone was removed.
Figure 5 (C1) The CAD/CAM plate was removed 14 weeks after surgery when the fistula was productive again. (C1–C3) A sharp demarcation line caudal to the crestal edge of the plate became visible and was conspicuous. (C2) Between the fibula segments, an incipient ossification of the gap was observed. The underlying bone was pale. (C3) The bone was removed caudally. The bone marrow was replaced by granulation tissue and was removed. (C4) The intersegmental ossification was not yet sufficient so that stabilization again was necessary.
Figure 6 The following OPTs outline the clinical course of TFF in a 76-year-old patient in good general condition who suffered from osseous metastasis of prostate cancer and underwent FFF. (OPT 1) A pathologic fracture occurred after the removal of necrotic bone in the right lower jaw in the setting of bisphosphonate induced MRONJ stage III (treatment with Zoledronacid/Denosumab in prostate cancer) [28]. (OPT 2) Virtual planning of double-barrel fibula was performed. CAD/CAM plate was used for stabilization and the simultaneous insertion of two dental implants was performed. (OPT 3) At 3 weeks post-surgery, the skin paddle was lost. A surgical exploration ended with the removal of an avital distal graft segment and modification of the plate in situ. The vascular pedicle of the remaining FFF still rendered a clear signal in the Doppler ultrasonic probe. (OPT 4) At 16 weeks after surgery, the remaining graft segment also had to be removed in the setting of continued inflammation and the absence of a Doppler signal. (OPT 5) At 22 weeks after surgery: The screws loosened in the anterior mandible segment so that the remaining plate with teeth 32–42 and a bone sequester had to be taken out.
Figure 7 Partial or total flap failure in relation to the number of fibula segments (p = 0.114).
Figure 8 Kaplan–Meier function was drawn for the three sub-groups of PFF. The abscissa axis “time” (days) is drawn on a logarithmic scale.
Figure 9 Comparison of the onset of adjuvant radiation therapy between the groups of complete flap success (n = 40) and PFF skin (n = 4).
Figure 10 TFF concerning the first clinical signs of flap necrosis and time of removal of the avital graft was visualized by Kaplan–Meier function. The abscissa axis “time” (days) is drawn on a logarithmic scale.
Figure 11 TFF analysis. Clinically diagnosed flap necrosis and further surgical interventions (removal of graft) are shown according to jaw location (maxilla or mandible) in the postoperative time course. The ordinate axis “time” (days) is drawn on a logarithmic scale.
cancers-13-00865-t001_Table 1Table 1 Clinical details of partial (PFF; n = 16) and total flap failures (TFF; n = 20) after jaw reconstruction with fibular free flaps.
N = 36 PFF
N = 16 (44.4%) TFF
N = 20 (56.6%) p-Value
Age (years), SD 59.9 ± 14.4 62.5 ± 9.5 p = 0.520
Follow-up (months), SD 48 ± 42.9 31.5 ± 31.6 p = 0.193
Type of flap loss
PFF, Skin paddle 11
PFF, Bone segment 4
PFF, Both 1
Total flap loss (TFF)
20
Sex
Female 5 6 p = 0.609
Male 11 14
Diagnosis
Benign tumor
Malignant tumor
MRONJ
ORN 1
15
15
2
3
Reconstruction
Immediate 14 17 p = 0.610
Delayed 2 3
Reconstruction
Non-VSP 10 10 p = 0.341
VSP 6 10
Neck dissection
Unilateral 11 13 n.s.
Bilateral 3 3
None 2 4
Tracheostomy
None 6 8 n.s.
Primary 9 11
Secondary 1 1
Irradiation
Preoperative 1 3 n.s.
Postoperative 8 4
None 7 13
Risk factors
Alcohol abuse 5 9 p = 0.348
Tobacco abuse 9 13 p = 0.546
Operating time (min) 546.2 ± 94.9 524.4 ± 97.2 p = 0.504
Duration ICU (days) 2 ± 1.3 2.1 ± 1.7 p = 0.847
Hospitalization (days) 22.6 ± 9.7 33.8 ± 18.8 p = 0.038
BMI
≤18
18 ≤ 25
25 ≤ 30
30 ≤ 35
>35
9
3
4
1
9
7
2
1
ASA-Score
ASA 2 10 7
ASA 3 6 12
ASA 4
1
n.s. = not significant; ORN, Osteoradionecrosis; MRONJ, Medication-related osteonecrosis of the jaw; VSP, virtual surgical planning; BMI, Body mass index; SD, standard deviation.
cancers-13-00865-t002_Table 2Table 2 Table depicting the locations according to the classification by Brown et al. where PFF (n=16) and TFF (n=20) occurred [29,30].
Type of Defect PFF Skin (n = 11) PFF Bone (n = 4) PFF Both (n = 1) TFF (n = 20)
Maxilla
II 1 - - 2
III 1 - - 1
Mandible
I
4
-
1
7
Ic - - -
1
II
2
2
-
6
IIc - 1 - -
III
3
1
- 2
IV - - -
1
cancers-13-00865-t003_Table 3Table 3 Clinical details of total flap failures (n = 20).
N = 20 Maxilla (n = 3) Mandible (n = 17) Overall (n = 20)
p
Age (years), SD 73.3 ± 1.8 60.6 ± 8.9 62.5 ± 9.5 p = 0.001 ^
Follow-up (months), SD 10.3 ± 9.7 35.2 ± 32.8 31 ± 31.6
The earliest sign of flap dysfunction (days) 3. 3 ± 3.5
(Median 3) 14.4 ± 11.1
(Median 10) 12 ± 10.9
(Median 8.5) p = 0.007 ^
Surgical validation and avital flap treatment procedure (days) 54 ± 60.1
(Median 36) 92.1 ± 132.0
(Median 21) 86.5 ± 123.6
(Median 22.5) p = 0.449 ^
Anastomosis revisions 2 6 8
Arterial thrombosis ‡ 2 2 4
Venous thrombosis ‡ - 4 4 n.s
Unknown 1 11 12
Explantation of bone graft 2 16 18
Osteosynthesis (PSI) removal 1 11 12
Re-osteosynthesis - 3 3
Second flap 1 8 9
Temporalis muscle flap 1 1 2
Deltopectoral flap - 1 1
Pectoralis major flap - 2 2
RFF - 1 1
FFF - 2 2
Hip graft (non-DCIA) - 1 1
‡ Kind of thrombosis was evaluated during microsurgical revision. (n.s. = not significant; ^ Equal variances not assumed; DCIA, deep circumflexia iliac artery; PSI, patient-specific implant; SD, standard deviation; RFF, radial forearm flap).
cancers-13-00865-t004_Table 4Table 4 Overview of FFF total and partial flap failure rates in the literature.
Authors Investigation Period
n
Total Flap Failure Partial Flap Failure
This study 2002–2020 180 11.1% 8.9%
Colletti et al. [16] 2002–2010 99 7% 3%
Gallegos-Hernandez et al. [35] 1996–2006 87 16.1% -
Götze et al. [12] 2013–2015 24 12.5% 8.3%
Lopez-Arcas et al. [36] 1992–2006 117 - 8.5%
Momoh et al. [23] 2005–2009 157 1% 14%
Mücke et al. [37] 2009–2013 76 9.2% -
Seruya et al. [22] 2003–2012 68 4.41% 11.76%
Shroff et al. [14] 2009–2013 30 6.66% -
Verhelst et al. [21] 1996–2016 129 12.4% 7.8% | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33670721 | 19,661,708 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pathological fracture'. | Partial and Total Flap Failure after Fibula Free Flap in Head and Neck Reconstructive Surgery: Retrospective Analysis of 180 Flaps over 19 Years.
Fibula free flap (FFF) is widely used in head and neck reconstructive surgery and is considered as a standard and therapy of choice after ablative cancer surgery. The aim of this retrospective monocenter study was to determine the success rates of fibula free flaps for jaw reconstruction after ablative tumor surgery. The disease course of patients who underwent jaw reconstructive surgery with FFF from January 2002 to June 2020 was evaluated regarding the flap success rate. Flap failure was analyzed in detail and categorized into two groups: partial flap failure (PFF) and total flap failure (TFF). A total of 180 free fibular flaps were performed over the last 19 years and a total of 36 flap failures were recorded. TFF occurred in n = 20 (56.6%) and PFF in n = 16 cases (44.4%) cases. No statistically significant differences were found concerning patients' age at flap transfer, sex, BMI, ASA-Score, preoperative non-virtual or virtual surgical planning (non-VSP vs. VSP), and time of reconstruction (immediately vs. delayed). Duration of hospitalization shows statistically significant differences between both groups (p = 0.038), but no differences concerning operating time and duration on Intensive Care Unit (ICU). Partial flap failure appears to be underreported in literature. Sub- and complete failure of the skin paddle leads to clinical complaints like uncovered bone segments and plate exposure. Partial or complete FFF failure lead to infections on the recipient site and prolonged wound healing and therefore may cause a delay of the beginning of adjuvant radiation therapy (RT). PFF of hard tissue can be induced by RT.
1. Introduction
Since the first mandibular reconstruction with a fibula free flap (FFF) by Hidalgo in 1989, it has been shown that FFF is a reliable and versatile graft [1,2]. Currently, FFF is considered as standard therapy in head and neck reconstructive surgery, providing the optimal precondition for dental implant success and therefore for oral and dental rehabilitation [3,4]. Long-term complications on the donor-site are relatively low. Most patients have been satisfied with the functional and aesthetic results [5,6]. The number of free tissue transfers of soft and/or bone tissue defects have increased significantly in recent years [7]. The flap provides the opportunity to include a septo-cutaneous skin paddle of up to 200 cm2. Cadaver studies investigating skin perfusion through selective injection have shown that a skin area of 12 × 7 cm can be perfused by a single perforating vessel [8]. A recent milestone in operative techniques is the possibility of computer-assisted surgery (CAS) and virtual surgical planning (VSP) in reconstructions of jaws [9,10,11]. VSP initially focused on bone grafts. The innovative potential lies in the design of a cutting guide that takes into account the course of the cutaneous perforating vessels based on preoperative CT and sonographic measurements [12,13]. For skin paddle harvesting, the support of perforator vessels is crucial. Fibular flaps have been reported to allow a success rate of up to 95% [7,14,15,16]. The causes of flap failure are anastomosis insufficiency, more frequent venous congestion (e.g., edema, hematoma), rare arterial occlusion (e.g., embolism, thrombus, kinking), vasospasms, postoperative bleeding, and coagulopathies [17,18,19,20].
However, detailed data about partial FFF loss are rare and seem to be underreported in literature. An analysis of risk factors for flap failure and complications in a low-level center of 129 FFFs over a time span of 20 years reported a PFF rate of 7.8%. By definition, (sub-)total flap loss describes the failure of the skin paddle and/or the loss of one or more bone graft segments in poly-segmental reconstructions [21]. The data published to date lack a differentiation concerning soft and/or hard tissue loss. A comparative investigation on computer-assisted versus conventional FFF technique for craniofacial reconstruction found six skin paddle and two segmental graft failures, which corresponded to a PFF rate of 11.76% (n = 8 out of 68) and a TFF rate of 4.41% (n = 3) [22]. Comparative results of partial loss were reported with a range of 3–14% [16,23]. This should be considered when the often-described advantage of the skin paddle as a vital monitor is advocated [24,25]. Gennaro et al. mentioned that a thin muscle cuff around bone, e.g., the fibula or vascularized iliac crest bone flap, is needed for flap harvesting. In these cases, a direct clinical assessment even without the use of a Doppler probe is advisable [26]. However, if PFF or TFF occurs, therapeutic options and decisions must be made to reduce local infection, functional impairment, and increase the patient’s quality of life. In this study, we have assessed and discussed the therapeutic options in the setting of TFF.
The aims of this study are:to estimate the rate of partial flap loss ((sub-)total loss of skin paddle and/or failure of graft segments) and total flap failure over a long time period of 19 years, and to suggest further therapy procedures according to localization and defect type;
to examine a correlation between age at flap transfer, BMI, ASA-Score, and risk factors in terms of partial and total flap failure; and
to investigate whether there is a correlation between non-VSP vs. VSP and time of reconstruction (immediate vs. delayed).
2. Materials and Methods
2.1. Study Design and Patient Population
The study was conducted as a monocentric, retrospective study. Medical records of all patients who underwent FFF in the head and neck region from January 2002 to June 2020 were analyzed in respect of success of the flap transfer procedure. Flap failure was stratified into two groups: partial flap failure (PFF) and total flap failure (TFF) (Figure 1). PFF was defined as any loss of parts of the skin paddle (Skin) (Figure 2), parts or segments (poly-segmental reconstruction) of bone grafts (Bone) (Figure 3), or a combination of both (Both). The major characteristic of PFF is the remaining blood supply by the vascular pedicle. In contrast to PFF, TFF is characterized by discontinued perfusion of the graft (i.e., thrombosis). Intra- or extraoral wound dehiscences around the skin paddle alone did not match the criteria for PFF and were not included.
All patients underwent a preoperative CT or MRI angiography to ensure the presence of a three fibular vessel anatomy and the absence of significant arteriosclerotic changes in the lower leg. Free fibula flap dissection was performed by Gilbert’s lateral approach [27]. To preserve knee and ankle stability, respectively, a bone length of 8 cm proximal to the harvest site and a distal bone length of 6–8 cm of distal to the harvest site were left in situ. When an osseo-cutaneous free flap was harvested, a muscle cuff with parts of soleus and flexor hallucis longus muscle was included to protect the perforators. Before donor-site wounds were closed, a vacuum drainage (Redon) was installed. Wound closure at the lower limb was performed using a split skin graft over the harvested skin flap or primarily in all cases of sole bone flaps without skin paddles.
Examples for the clinical course of a subtotal bone graft loss (PFF) were illustrated in Figure 3, Figure 4 and Figure 5 and an example of TFF is demonstrated in Figure 6.
2.2. Study Parameters and Evaluator Calibration
The following parameters were collected: Patient age at the time of flap transfer, sex, primary diagnosis, planning procedure, location, type of defect classified according to Brown et al. [29,30], number of fibula segments, reconstruction time (immediately vs. delayed), flap condition, part of flap loss, and reason for flap loss. Patients’ medical records were analyzed independently for flap outcomes.
2.3. Inclusion and Exclusion Criteria for Study Subjects
In this study, we enrolled all patients who underwent a reconstruction of the maxilla or mandible (immediately or delayed) with a FFF. Only cases with incomplete data sets and/or medical records were excluded (n = 2).
2.4. Statistical Analyses
Fischer test and Freeman–Halton extension [31] were used to compare flap outcome with sex, ASA-Score, alcohol and tobacco abuse, time and method of reconstruction, and the number of fibular bone segments. Students t-test was performed to compare the mean age at FFF-transfer, operating time, duration in the ICU, and time of hospitalization between the three flap outcome groups after verification of normality. p < 0.05 was defined as statistically significant. The statistical analysis was carried out with SPSS 25 (SPSS Inc., Chicago, IL, USA).
2.5. Ethics Statement/Confirmation of Patients’ Permission
The study was approved by the local Ethics Committee of the Justus-Liebig University Giessen (AZ35/20) and patients’ consent was not necessary for this retrospective study. The patients consented that their intraoral pictures and X-ray images may be used anonymously in the publication. All data in the Microsoft Excel spreadsheet were pseudonymized.
3. Results
A total of 180 fibula free flaps (FFF) were performed over a period from January 2002 to June 2020. Complete flap success was recorded in 144 cases (80.0%). The remaining 36 flap failures were categorized into the two major groups partial (PFF) and total flap failure (TFF). PFF occurred in n = 16 (44.4%) and TFF in n = 20 (56.6%) cases (Table 1). No statistically significant difference concerning the age at flap transfer, sex, time, and method of reconstruction was apparent. Furthermore, no significant differences were detected in relation to surgical parameters (neck dissection, tracheostomy, radiation therapy) and general risk factors (alcohol and tobacco abuse). There is a significant difference concerning the duration of hospitalization between the groups PFF (mean 22.6 ± 9.7 days) and TFF (mean 33.8 ± 18.8 days) (p = 0.038). No statistically significant differences concerning operating time and duration in the ICU between PFF and TFF were detected.
While TFF occurred in a median 8.5 days, PFF was clinically incident later. All TFF were an early complication. Out of 20 TFF (100%), four arterial and four venous thrombosis were found during anastomosis revision. The aetiology of the flap failure of the remaining 12 cases (60%) are unknown. PFF of the skin paddle (n = 11) was observed in a median time of 22.5 days and therefore considered as a late complication. The onset of PFF of bone segments without skin paddles (n = 4) was detected much later at a median time of 101.5 days.
PFF was analyzed in detail. After maxillary reconstruction, two partial and three total flap failures were found in the investigation. This corresponds to 13.5% (n = 5) of the study collective. Two cases of PFF of the skin paddle was found after maxilla reconstructions (Brown Class II and III) with uni-segmental fibular, and three TFF were observed in uni- (n = 2) and bi-segmental reconstruction (n = 1).
In mandible reconstruction, PFF was observed in 87.5% of cases. A total number of 14 partial flap failures—nine losses of the skin paddle, four isolated bone graft losses, and one combination of both—were found in mandible reconstructions after tumor recurrence (Table 2). Out of 11 skin paddle losses (PFF), 81.81% (n = 9) occurred in the conventional non-VSP group.
TFF was observed mostly in Brown class I (n = 7) and II (n = 6) defects. Subtotal loss of the skin paddle was incident in 68.7% of cases (n = 11 out of 16). Isolated loss of fibular bone segments was found in 25.0% (n = 4) and a combination of both was reported in only one case (6.3%). PFF was found in 50.0% (8 out of 16 cases) of uni-segmental, 25.0% (n = 4) of bi-segmental, and 25.0% (n = 4) of tri-segmental jaw reconstructions. A total flap loss occurred in 55.0% of cases after bi-segmental and in 40.0% of cases after uni-segmental reconstructions (Figure 7). There was a non-significant trend towards TFF in poly-segmental reconstructions (p = 0.114).
A total loss of the skin paddle (n = 11) was observed at a mean of 27 days (median 22 days, range 2–67 days) and an isolated loss of bone graft segments at 181 days (n = 4; median: 101.5 days, range 37–499 days) post surgery. Kaplan–Meier survival function was calculated and visualizes the different periods of partial soft and hard tissue failure (Figure 8).
In comparison to the beginning of radiation therapy in the complete success group (n = 40, mean 52.9 days, median 49 days, range 21–98 days), PFF of the skin paddle generates a delay (Figure 9). Radiation therapy started at a mean of 63.5 days (n = 4, median 50.5 days, range 39–114 days). The difference remains without any statistical significance (p = 0.358).
Clinical flap necrosis and time of bone graft removal were compared with the number of bone segments used. Statistical analysis showed no significant differences between the uni- and bi-segmental graft losses. Overall, clinical flap loss was observed at a mean of 12 days after surgery (Median 8.5 days, range 0–40 days) and surgical removal of the avital grafts at a mean of 86.4 postoperative days (Median 22.5 days, range 2–503 days) (Figure 10).
Comparing TFF after maxillary and mandibular reconstruction, it is noticeable that maxillary TFF cases were a mean of 73.3 years old, and thus older than mandibular TFF cases (62.5 years). Therefore, with unequal variance, there is a statistically highly significant difference, which can be explained by the composition of the collective (p < 0.001). Regarding the first clinical sign of impending TFF, signs of TFF were documented after 3.3 days in the upper jaw and after 14.4 days in the lower jaw (Table 3). This observation is statistically significant (p = 0.007). Concerning further surgical procedure and removal of the necrotic graft, no statistically significant difference between maxilla and mandible was observed (Figure 11).
4. Discussion
4.1. Rate of PFF and TFF
Thrombosis, kinking, and spasm of the vessels have been reported as common causes of total free-flap failure in the early phase after microvascular anastomosis [32]. Venous thrombosis is more common than arterial thrombosis due to the low-flow and low-pressure venous system. Unrecognized venous thrombosis can lead to backward perfusion failure up to total stasis in the arterial system. This is followed by flap ischemia, no-reflow, and subsequent flap loss [33,34]. Fibular flaps are reported with success rates of up to 95.0% [7,14,15,16]. Study findings have shown a cumulative success rate of 88.9% (80.0% complete success and 8.9% partial flap failure). The total failure rate in the presented study is 11.1% over the last 19 years and over all types of indications for reconstruction, time of reconstruction, and method of planning (Non-VSP vs. VSP). In comparison to the here reported investigations, other reconstructive centers report total fibular flap failure rates of up to 12.4% (Table 4). Comparability of the results must be ensured concerning the chosen definition of flap success and PFF/TFF. In the presented study, strict criteria for PFF and TFF was defined. Only clear definitions will engage the collection of comparable data. Retrospective study design without standardization is often of poor data quality due to incomplete follow up data and different investigators. However, data collection over 19 years by a single investigator appears to be impractical. Loss and removal of the whole graft are clear parameters for TFF. From the clinical course and as a result of perfusion disorder through its vascular pedicle, TFF is an early flap failure. Therefore, minor, insufficient perfusion of flap elements leads to malnutrition, and thus to consecutive (sub-)total loss of skin paddle and/or bone segments. This was defined as PFF. PFF therefore does include the functional use of the flap and appears as a late flap failure. Most published data lack a differentiation between soft and hard tissue loss. Partial flap failure was reported with an incidence of 3–14% but has not been further differentiated in most cases (Table 4).
A retrospective single-center study on 129 FFF transfers over the last 20 years found TFF in 12.4% and PFF in 7.8% of cases [21]. An investigation on 20 virtual planned FFF showed that preoperative planning based on preoperative CT-scan allows to include the preoperatively planned skin paddle area [13]. Another clinical trial included preoperatively marked perforator vessels for skin paddle in digital planning and noted a survival rate of 92% (n = 24) in FFF transfer with three total and two partial skin paddle losses [12]. Other investigators observed seven total flap losses and three losses of skin paddle in a total of 99 FFFs [16].
In the present study, there were four losses of fibular bone segments and only two of them occurred after radiation therapy (RT). Loss of the skin paddle occurred in two cases of maxillary reconstruction and in nine cases of uni- and poly-segmental reconstruction of the mandible. After an average time of 27 days (median: 22 days, range 2–67 days), partial loss of the skin paddle was observed whereas partial bone loss occurred after mean 181 days (Median: 101.5 days, range 37–499 days). Swelling and edema are results of ongoing inflammatory processes and wound healing immediately after surgery. A critically reduced perfusion of the septo-cutaneous perforators could be the consequence. Its maximum dimension can be expected 2–3 days after surgery. The unusually late appearance of visible (sub-)total dysfunction of the skin paddle perfusion after more than the median time of 3 weeks should be interpreted with caution and as result of documentation bias. Any influence of RT in this respect can be excluded, since RT always started after PFF was already observed. The onset of adjuvant RT in the group PFF skin was at median 50.5 days (range 39–114 days) after surgery in comparison to the control group comprising complete flap success (n = 40), in which RT began in median 49 days (range 21–98 days) after surgery. A statistically significant difference could not be observed. However, an adjuvant RT for oncologic reasons was not to be delayed by a PFF. The results must be interpreted with caution due to the small number of cases. In the literature, the effect of prior irradiation on partial or complete loss of FFF compared with unirradiated grafts has often been reported to be statistically insignificant [38,39,40,41,42]. The effect of postoperative irradiation on partial flap failure in microvascular head and neck reconstruction has not been well described in literature and indicates that further studies are needed in this area. Verhelst et al. focused on perioperative irradiation but it was not identified as a statistically insignificant risk factor for flap failure [21]. In a study by He et al., 9 of 17 patients were irradiated postoperatively and all grafts sustained [43]. In this study, no cases of PFF were detected during or after RF. Under RT conditions, PFF could be similar to radiogenic oral mucositis, which is associated with an early inflammatory response [44,45]. These factors provide a target for biology-based mucositis-prevention strategies [46,47], and thus for PFF prevention. Further, the option of an additional skin paddle for defect closure after oncologic resection is without doubt one of the major advantages of the FFF in addition to its clinical and technical function of flap monitoring. On the other site, wound healing disorder of the donor site after skin paddle harvesting appears at a rate of 1.07–31.2% [23,48,49]. In literature, different techniques for closure of the donor site have been described [50]. Focused only on monitor function, the price for an unreliable monitor skin paddle seems to be high and should be critically reflected. Nevertheless, some authors believe that the reliability of the skin paddle for the closure of recipient site defects is insufficient in non-irradiated [51] and especially in irradiated patients [52]. In a retrospective investigation, Thome et al. observed 20% of skin paddle failures (n = 27) and came to a similar conclusion [53]. Other authors found a stable and sufficient vascular supply of the septo-cutaneous skin paddle by the septum intermusculare posterius and perforator vessels around the musculus soleus [54,55,56]. They emphasize the necessity of a muscle cuff around the posterior septum, which contains vessels that are crucial for skin paddle survival [24].
Partial bone loss may occur more frequently than previously observed and described in the literature as a result of malnutrition. Sufficient neovascularization to allow free-flap survival independent of the vascular pedicle has been reported to occur within 7 to 10 days in myo-cutaneous flaps [57,58,59]. In contrast, a comparative prospective clinical study measured hemoglobin oxygenation and capillary flow in 50 flaps (25 forearm flaps, 15 osseo-cutaneous fibular flaps, and 10 anterolateral thigh flaps) at 4 and 12 postoperative weeks. The authors found that flap autonomization rates were significantly higher in the lower jaw and non-irradiated defect sites. In addition, fascio-cutaneous flaps were found to be autonomized faster than osseo-myo-cutaneous free flaps. Myo-cutaneous flaps were never found to be autonomized after 4 weeks [60]. Kumar et al. studied blood supply of fascio-septo-cutaneous free flaps several months after surgery and found no significant blood flow through vessels across the flap inset [59]. Mücke et al. found that osseo-myo-cutaneous free flaps are significantly dependent on vascularity of the original anastomoses even 1 year after surgery [60]. According to their data, our findings should be interpreted as an adverse effect of radiation therapy (n = 2) and two “real” partial bone segment failures. The risk to develop osteoradionecrosis is decreased in patients with high body mass indices and on steroid therapy [61] through adequate soft-tissue bulk paired with the high-quality vascularized fibula bone [62]. Data published in the literature show that osteoradionecrosis of the original mandible occurred after a median time of 10.9 months (range 1.8–89.7 months) after RT and 90% occurred within 37.4 months [63]. In contrast, our data show bone loss after a median time of 3.38 months (range 1.23–16.63 months) and more than 6 months earlier. This observation should be interpreted with caution due to the low number of cases and should be further studied in larger study groups.
Early TFF was incident in n = 3 maxillary and n = 17 mandible reconstructions. TFF was found after mandible reconstruction in anterior defects (Classes III-IV, 3 out of 17 cases, 17.6%) and more frequently in lateral defects (Classes I–II, n = 14, 82.4%). Uni- and bi-segmental were commonly used for these Classes I–II reconstructions. Reasons for increased TFF in class I and II were critical pedicle course (inner surface of mandible and mouth floor), kinking of the vascular bundle [64] and length [21,65,66]. In addition to known general risk and complicating factors, further risk factors for flap failure include postoperative swelling and edema, hematoma, movement of the neck, circular tracheal tube fixation loop, and course of the vessel through the neck [33].
The therapeutic procedure for partial skin or isolated bone loss depends on the jaw affected. If PFF of the skin paddle occurs in the maxilla, it is usually an uncritical situation and wound healing from peri-osseous tissue can be expected. When bone loss in the maxilla occurs, a “simple” prosthetic rehabilitation by obturator prosthetic is a therapeutic alternative [67,68] if another microvascular bone graft is not desired. Large defects can be downsized with local tissue advancement. Functional impairment (eg. scars) might be addressed in a two-staged procedure. Safe flaps routinely used in our department are the temporal myo-fascial [69], pectoralis major [70,71], and deltopectoral flaps [72].
In the mandible, skin paddle loss is often noncritical when the primary bone graft is vital. After wound healing local flaps and staged scars, loosing procedures can be necessary to improve dysfunction such as trismus [73]. Flaps of choice in this situation are often radial forearm [74], pectoralis major [70,71], and deltopectoral flaps [72]. When PFF of bone segments or TFF after mandible reconstructions appear, there are different strategies available that need to be evaluated in light of the patient’s condition. If patient’s condition is poor and the avital graft showed no signs of inflammation, it was left in the oral cavity (Figure 6). If inflammation and/or loosening of osteosynthesis material occurred around the avital segment, removal is necessary. Sometimes further use of osteosynthesis is possible, especially if patient-specific osteosynthesis was used. However, in the majority of cases, removal of the osteosynthesis will become necessary (Table 3). Re-osteosyntheses could be useful in combination with distant flaps like pectoralis major flaps, deltopectoral flaps, and bone hip grafts. The staged procedure of second attempts microvascular bone graft is possible after critical evaluation. The removal of the avital graft and the anticipation of stable scars building and “functional” pseudarthrosis is a further option (Figure 6).
4.2. Influence of Age at Flap Transfer, BMI, ASA-Score and Risk Factors in Terms of Flap Success in Relation to PFF and TFF
In this study, no significant differences between patients’ age at flap transfer and flap outcome were observed. This confirms other investigations that patients’ age at flap transfer is not crucial for flap success [75,76]. It is a surrogate parameter for the general condition of the patient [77,78]. A prospective study on 215 patients found that age ≥ 70 years had a significantly higher ASA-Score and shorter duration of surgery. Age was a risk factor for longer ICU stay and complication rate. They found no influence of age on the length of hospital stay and overall success of microvascular reconstructions [79]. In this study, more than 92% were rated ASA 2 or 3. All partial flap failures and all but one total flap occurred in both groups. ASA score and duration of the operation were found to be independent risk factors for operative revisions [76]. In literature, ASA-Rating is correlated with a higher number of postoperative complications after microvascular reconstructions [80,81] and the overall survival [82]. We calculated the relation between ‘Age at flap transfer’ and BMI and found an evenly distributed pattern.
Concerning alcohol and tobacco abuse in the investigated group, no statistically significant differences were found. In published literature, alcohol abuse was identified as a risk factor for postoperative adverse events [82]. Tobacco abuse was shown to reduce overall survival time compared with non- and never-smokers [83,84]. A review by Van Imhoff et al. stated that survival rates are lower and recurrence rates are higher in patients who continued to smoke after having being diagnosed with Head and Neck SCC in comparison to patients who stopped smoking [85].
BMI had no statistically significant influence on flap success in this study. Low BMI or underweight at diagnosis was an independent, unfavorable prognostic factor [86,87]. Obesity was associated with better outcome and was not an independent risk factor for postoperative complications of free tissue transfer [88,89]. Other investigators found that higher BMI/obesity is a risk factor for peri- and postoperative medical complications [90].
The duration of hospitalization was calculated with a mean of 22.6 days in the PFF group and a mean of 33.8 days in the TFF group. Statistically significant differences (p = 0.038) were found in the occurrence of partial or total flap failures (Table 1). While the majority (68.75%, n= 11 out of 16) of all partial flap failures are a dysfunction of the skin paddle failures (mean duration of hospitalization partial flap loss group 20.71 days), we conclude that loss of that skin loss does not result in significantly longer hospital stay than in total flap losses. Stepwise removing of avital flap parts, deperiostizing of the bone graft, and covering with oral mucosa is an attempt for flap salvage. However, the initial stay at the ICU seems to have no statistical influence concerning upcoming PFF or TFF. It was calculated in both groups with a mean of approximately 2.0 days.
No statistically significant difference concerning mean operating time (PFF: meantime 546 min, TFF: meantime 524 min) and flap outcome was found. Surgery time is described as a risk factor for postoperative complications [91,92,93]. Increased operating time may also be the result of a younger surgeon learning and being taught by an older instructing surgeon. However, operating time should be reduced whenever possible [92]. The study could not include ischemia time in the risk analysis because this parameter was not recorded or was incomplete.
4.3. PFF and TFF in Non-VSP vs. VSP and Reconstruction Methods (Immediate vs. Delayed)
The majority of isolated skin paddle losses occurred in the non-VSP group. Reasons can be seen in mechanical trauma and manipulation during free-hand transplant forming i.e., preparation of bone segments and revised application of osteosynthesis. Individually custom-made cutting guides stabilize and preserve intersegmental connectors for stabilization of several bone segments, which provide a valuable support on the vascular pedicle during transplant preparation and shaping.
No statistically significant differences were found concerning patients’ preoperative planning procedure (non-VSP vs. VSP) and time of reconstruction (immediately vs. delayed). The results confirmed the findings of other clinical investigations [94]. A retrospective study of 128 osseous free flaps with a minimum follow-up of 12 months evaluated plate-related complications in patient-specific versus conventional fixation systems. They found more complications with patient-specific plates (e.g., wound healing disorders, plate exposure, fixation failure, and subtotal osseous union) in comparison to conventional reconstruction plates, but the differences were statistically insignificant.
One possible reason for (sub-)total bone loss despite maintained perfusion of the vascular pedicle might be trauma during preparation, segmentation, and shaping of the fibula graft. Preoperatively planned and fabricated saw guides and patient-specific implants ease and accelerate the surgical procedure itself, which should be helpful in avoiding mistakes and facilitating the handling of the fibula graft. More complex shaping and osteotomization of bone segments leads to manipulation of the vascular pedicle during dissection and puts it at risk [22]. Furthermore, the impact of VSP and patient-specific plates in terms of wound healing abnormalities, plate exposure, and subtotal osseous union shows a trend towards increased complication rates compared with non-VSP with hand-bended plates. Plate-related complications were increased with radiotherapy and multi-segment flaps [95].
Further investigations on partial flap loss of osseomyocutaneous FFF are needed.
5. Conclusions
The fibula free flap constitutes a standard therapy for jaw reconstructive surgery. The present results of 180 fibula free flap over a period of 19 years shows a cumulative success rate of 88.9%, which is well comparable with other studies. The findings of our long term monocenter retrospective investigation are a position statement about flap success and partial and total loss rates, which was achieved by careful patient selection and a two team approach to reduce operating time. In partial or total flap failure, no statistically significant correlation was observed between patient age, sex, ASA, BMI, alcohol and tobacco abuse, time, and method of reconstruction (virtual versus non-virtual surgical planning). Total flap failure caused significantly prolonged hospitalization time. Partial flap failure affected mainly the skin paddle. Two-thirds of these cases were found in the non-VSP group and only two cases were observed in the virtual surgical planning group. This could be attributed to protective effects of the cutting-guide template, which possibly decrease the mechanical trauma during surgery.
Acknowledgments
The authors are grateful for the consent of the patient for presented X-rays and clinical images. This publication is part of the second author’s dental doctoral thesis (SS).
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
Conceptualization, M.K.; methodology, S.S., M.K., C.B.; formal analysis, M.K.; investigation, M.K., and S.S; data curation, M.K. and S.S.; writing—original draft preparation, M.K., S.S., S.A. and S.B.; writing—review and editing, M.K., S.S., S.A., C.B., D.S., H.-P.H. and S.B.; visualization, M.K., D.S., H.-P.H. and S.A.; supervision, M.K., H.-P.H., S.B. and S.A.; project administration, M.K. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Justus-Liebig University Giessen (AZ35/20, approval 25.5.2020).
Informed Consent Statement
Patient consent was waived as the study is a retrospective data analysis.
Data Availability Statement
The data presented in this study are available upon request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Schematic illustration of reconstructive workflow and stratification in partial and total flap failure groups. The major characteristic of PFF is the remaining blood supply by the vascular pedicle. In contrast to this, TFF is characterized by interrupted graft perfusion.
Figure 2 Example of ‘PFF skin’ after maxilla reconstruction.
Figure 3 The clinical course of PFF. (OPT 1) Due to the recurrence of an ossifying fibroma (odontogenic tumor) in the ramus ascendens mandibulae in a 22-year-old patient, (OPT 2) a continuity resection and simultaneous reconstruction with a bi-segmental fibula and CAD/CAM plate was planned. (OPT 3) The clinical submandibular fistula had a connection to the plate (Figure 4A). (OPT 4) An OPT image was obtained after removal of the avital fibular segments and re-stabilization of the remaining graft. There is initial evidence of incipient bone healing on the proximal resection-site. (OPT 5) Follow-up visit at 9 weeks after re-stabilization. In the condylar segment, bone healing is pictured, and at the distal segment, progressive resorption is visible. (OPT 6) Progressive bone healing and callus formation originating from the resection site is visible 19 weeks after re-stabilization.
Figure 4 (A) Clinical aspect 4 weeks after reconstruction. After reopening the submandibular approach and excision of the skin fistula, there was no evidence of screw loosening. Temporary unscrewing of the screw (No. 5) leads to bleeding. (B) With a new fistula, the site was reentered 8 weeks after surgery and the screw was removed again. There was no clear bleeding from the screw hole. In addition, the anterior-caudal edge of the bone was removed.
Figure 5 (C1) The CAD/CAM plate was removed 14 weeks after surgery when the fistula was productive again. (C1–C3) A sharp demarcation line caudal to the crestal edge of the plate became visible and was conspicuous. (C2) Between the fibula segments, an incipient ossification of the gap was observed. The underlying bone was pale. (C3) The bone was removed caudally. The bone marrow was replaced by granulation tissue and was removed. (C4) The intersegmental ossification was not yet sufficient so that stabilization again was necessary.
Figure 6 The following OPTs outline the clinical course of TFF in a 76-year-old patient in good general condition who suffered from osseous metastasis of prostate cancer and underwent FFF. (OPT 1) A pathologic fracture occurred after the removal of necrotic bone in the right lower jaw in the setting of bisphosphonate induced MRONJ stage III (treatment with Zoledronacid/Denosumab in prostate cancer) [28]. (OPT 2) Virtual planning of double-barrel fibula was performed. CAD/CAM plate was used for stabilization and the simultaneous insertion of two dental implants was performed. (OPT 3) At 3 weeks post-surgery, the skin paddle was lost. A surgical exploration ended with the removal of an avital distal graft segment and modification of the plate in situ. The vascular pedicle of the remaining FFF still rendered a clear signal in the Doppler ultrasonic probe. (OPT 4) At 16 weeks after surgery, the remaining graft segment also had to be removed in the setting of continued inflammation and the absence of a Doppler signal. (OPT 5) At 22 weeks after surgery: The screws loosened in the anterior mandible segment so that the remaining plate with teeth 32–42 and a bone sequester had to be taken out.
Figure 7 Partial or total flap failure in relation to the number of fibula segments (p = 0.114).
Figure 8 Kaplan–Meier function was drawn for the three sub-groups of PFF. The abscissa axis “time” (days) is drawn on a logarithmic scale.
Figure 9 Comparison of the onset of adjuvant radiation therapy between the groups of complete flap success (n = 40) and PFF skin (n = 4).
Figure 10 TFF concerning the first clinical signs of flap necrosis and time of removal of the avital graft was visualized by Kaplan–Meier function. The abscissa axis “time” (days) is drawn on a logarithmic scale.
Figure 11 TFF analysis. Clinically diagnosed flap necrosis and further surgical interventions (removal of graft) are shown according to jaw location (maxilla or mandible) in the postoperative time course. The ordinate axis “time” (days) is drawn on a logarithmic scale.
cancers-13-00865-t001_Table 1Table 1 Clinical details of partial (PFF; n = 16) and total flap failures (TFF; n = 20) after jaw reconstruction with fibular free flaps.
N = 36 PFF
N = 16 (44.4%) TFF
N = 20 (56.6%) p-Value
Age (years), SD 59.9 ± 14.4 62.5 ± 9.5 p = 0.520
Follow-up (months), SD 48 ± 42.9 31.5 ± 31.6 p = 0.193
Type of flap loss
PFF, Skin paddle 11
PFF, Bone segment 4
PFF, Both 1
Total flap loss (TFF)
20
Sex
Female 5 6 p = 0.609
Male 11 14
Diagnosis
Benign tumor
Malignant tumor
MRONJ
ORN 1
15
15
2
3
Reconstruction
Immediate 14 17 p = 0.610
Delayed 2 3
Reconstruction
Non-VSP 10 10 p = 0.341
VSP 6 10
Neck dissection
Unilateral 11 13 n.s.
Bilateral 3 3
None 2 4
Tracheostomy
None 6 8 n.s.
Primary 9 11
Secondary 1 1
Irradiation
Preoperative 1 3 n.s.
Postoperative 8 4
None 7 13
Risk factors
Alcohol abuse 5 9 p = 0.348
Tobacco abuse 9 13 p = 0.546
Operating time (min) 546.2 ± 94.9 524.4 ± 97.2 p = 0.504
Duration ICU (days) 2 ± 1.3 2.1 ± 1.7 p = 0.847
Hospitalization (days) 22.6 ± 9.7 33.8 ± 18.8 p = 0.038
BMI
≤18
18 ≤ 25
25 ≤ 30
30 ≤ 35
>35
9
3
4
1
9
7
2
1
ASA-Score
ASA 2 10 7
ASA 3 6 12
ASA 4
1
n.s. = not significant; ORN, Osteoradionecrosis; MRONJ, Medication-related osteonecrosis of the jaw; VSP, virtual surgical planning; BMI, Body mass index; SD, standard deviation.
cancers-13-00865-t002_Table 2Table 2 Table depicting the locations according to the classification by Brown et al. where PFF (n=16) and TFF (n=20) occurred [29,30].
Type of Defect PFF Skin (n = 11) PFF Bone (n = 4) PFF Both (n = 1) TFF (n = 20)
Maxilla
II 1 - - 2
III 1 - - 1
Mandible
I
4
-
1
7
Ic - - -
1
II
2
2
-
6
IIc - 1 - -
III
3
1
- 2
IV - - -
1
cancers-13-00865-t003_Table 3Table 3 Clinical details of total flap failures (n = 20).
N = 20 Maxilla (n = 3) Mandible (n = 17) Overall (n = 20)
p
Age (years), SD 73.3 ± 1.8 60.6 ± 8.9 62.5 ± 9.5 p = 0.001 ^
Follow-up (months), SD 10.3 ± 9.7 35.2 ± 32.8 31 ± 31.6
The earliest sign of flap dysfunction (days) 3. 3 ± 3.5
(Median 3) 14.4 ± 11.1
(Median 10) 12 ± 10.9
(Median 8.5) p = 0.007 ^
Surgical validation and avital flap treatment procedure (days) 54 ± 60.1
(Median 36) 92.1 ± 132.0
(Median 21) 86.5 ± 123.6
(Median 22.5) p = 0.449 ^
Anastomosis revisions 2 6 8
Arterial thrombosis ‡ 2 2 4
Venous thrombosis ‡ - 4 4 n.s
Unknown 1 11 12
Explantation of bone graft 2 16 18
Osteosynthesis (PSI) removal 1 11 12
Re-osteosynthesis - 3 3
Second flap 1 8 9
Temporalis muscle flap 1 1 2
Deltopectoral flap - 1 1
Pectoralis major flap - 2 2
RFF - 1 1
FFF - 2 2
Hip graft (non-DCIA) - 1 1
‡ Kind of thrombosis was evaluated during microsurgical revision. (n.s. = not significant; ^ Equal variances not assumed; DCIA, deep circumflexia iliac artery; PSI, patient-specific implant; SD, standard deviation; RFF, radial forearm flap).
cancers-13-00865-t004_Table 4Table 4 Overview of FFF total and partial flap failure rates in the literature.
Authors Investigation Period
n
Total Flap Failure Partial Flap Failure
This study 2002–2020 180 11.1% 8.9%
Colletti et al. [16] 2002–2010 99 7% 3%
Gallegos-Hernandez et al. [35] 1996–2006 87 16.1% -
Götze et al. [12] 2013–2015 24 12.5% 8.3%
Lopez-Arcas et al. [36] 1992–2006 117 - 8.5%
Momoh et al. [23] 2005–2009 157 1% 14%
Mücke et al. [37] 2009–2013 76 9.2% -
Seruya et al. [22] 2003–2012 68 4.41% 11.76%
Shroff et al. [14] 2009–2013 30 6.66% -
Verhelst et al. [21] 1996–2016 129 12.4% 7.8% | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33670721 | 19,661,708 | 2021-02-18 |
What was the outcome of reaction 'Osteonecrosis of jaw'? | Partial and Total Flap Failure after Fibula Free Flap in Head and Neck Reconstructive Surgery: Retrospective Analysis of 180 Flaps over 19 Years.
Fibula free flap (FFF) is widely used in head and neck reconstructive surgery and is considered as a standard and therapy of choice after ablative cancer surgery. The aim of this retrospective monocenter study was to determine the success rates of fibula free flaps for jaw reconstruction after ablative tumor surgery. The disease course of patients who underwent jaw reconstructive surgery with FFF from January 2002 to June 2020 was evaluated regarding the flap success rate. Flap failure was analyzed in detail and categorized into two groups: partial flap failure (PFF) and total flap failure (TFF). A total of 180 free fibular flaps were performed over the last 19 years and a total of 36 flap failures were recorded. TFF occurred in n = 20 (56.6%) and PFF in n = 16 cases (44.4%) cases. No statistically significant differences were found concerning patients' age at flap transfer, sex, BMI, ASA-Score, preoperative non-virtual or virtual surgical planning (non-VSP vs. VSP), and time of reconstruction (immediately vs. delayed). Duration of hospitalization shows statistically significant differences between both groups (p = 0.038), but no differences concerning operating time and duration on Intensive Care Unit (ICU). Partial flap failure appears to be underreported in literature. Sub- and complete failure of the skin paddle leads to clinical complaints like uncovered bone segments and plate exposure. Partial or complete FFF failure lead to infections on the recipient site and prolonged wound healing and therefore may cause a delay of the beginning of adjuvant radiation therapy (RT). PFF of hard tissue can be induced by RT.
1. Introduction
Since the first mandibular reconstruction with a fibula free flap (FFF) by Hidalgo in 1989, it has been shown that FFF is a reliable and versatile graft [1,2]. Currently, FFF is considered as standard therapy in head and neck reconstructive surgery, providing the optimal precondition for dental implant success and therefore for oral and dental rehabilitation [3,4]. Long-term complications on the donor-site are relatively low. Most patients have been satisfied with the functional and aesthetic results [5,6]. The number of free tissue transfers of soft and/or bone tissue defects have increased significantly in recent years [7]. The flap provides the opportunity to include a septo-cutaneous skin paddle of up to 200 cm2. Cadaver studies investigating skin perfusion through selective injection have shown that a skin area of 12 × 7 cm can be perfused by a single perforating vessel [8]. A recent milestone in operative techniques is the possibility of computer-assisted surgery (CAS) and virtual surgical planning (VSP) in reconstructions of jaws [9,10,11]. VSP initially focused on bone grafts. The innovative potential lies in the design of a cutting guide that takes into account the course of the cutaneous perforating vessels based on preoperative CT and sonographic measurements [12,13]. For skin paddle harvesting, the support of perforator vessels is crucial. Fibular flaps have been reported to allow a success rate of up to 95% [7,14,15,16]. The causes of flap failure are anastomosis insufficiency, more frequent venous congestion (e.g., edema, hematoma), rare arterial occlusion (e.g., embolism, thrombus, kinking), vasospasms, postoperative bleeding, and coagulopathies [17,18,19,20].
However, detailed data about partial FFF loss are rare and seem to be underreported in literature. An analysis of risk factors for flap failure and complications in a low-level center of 129 FFFs over a time span of 20 years reported a PFF rate of 7.8%. By definition, (sub-)total flap loss describes the failure of the skin paddle and/or the loss of one or more bone graft segments in poly-segmental reconstructions [21]. The data published to date lack a differentiation concerning soft and/or hard tissue loss. A comparative investigation on computer-assisted versus conventional FFF technique for craniofacial reconstruction found six skin paddle and two segmental graft failures, which corresponded to a PFF rate of 11.76% (n = 8 out of 68) and a TFF rate of 4.41% (n = 3) [22]. Comparative results of partial loss were reported with a range of 3–14% [16,23]. This should be considered when the often-described advantage of the skin paddle as a vital monitor is advocated [24,25]. Gennaro et al. mentioned that a thin muscle cuff around bone, e.g., the fibula or vascularized iliac crest bone flap, is needed for flap harvesting. In these cases, a direct clinical assessment even without the use of a Doppler probe is advisable [26]. However, if PFF or TFF occurs, therapeutic options and decisions must be made to reduce local infection, functional impairment, and increase the patient’s quality of life. In this study, we have assessed and discussed the therapeutic options in the setting of TFF.
The aims of this study are:to estimate the rate of partial flap loss ((sub-)total loss of skin paddle and/or failure of graft segments) and total flap failure over a long time period of 19 years, and to suggest further therapy procedures according to localization and defect type;
to examine a correlation between age at flap transfer, BMI, ASA-Score, and risk factors in terms of partial and total flap failure; and
to investigate whether there is a correlation between non-VSP vs. VSP and time of reconstruction (immediate vs. delayed).
2. Materials and Methods
2.1. Study Design and Patient Population
The study was conducted as a monocentric, retrospective study. Medical records of all patients who underwent FFF in the head and neck region from January 2002 to June 2020 were analyzed in respect of success of the flap transfer procedure. Flap failure was stratified into two groups: partial flap failure (PFF) and total flap failure (TFF) (Figure 1). PFF was defined as any loss of parts of the skin paddle (Skin) (Figure 2), parts or segments (poly-segmental reconstruction) of bone grafts (Bone) (Figure 3), or a combination of both (Both). The major characteristic of PFF is the remaining blood supply by the vascular pedicle. In contrast to PFF, TFF is characterized by discontinued perfusion of the graft (i.e., thrombosis). Intra- or extraoral wound dehiscences around the skin paddle alone did not match the criteria for PFF and were not included.
All patients underwent a preoperative CT or MRI angiography to ensure the presence of a three fibular vessel anatomy and the absence of significant arteriosclerotic changes in the lower leg. Free fibula flap dissection was performed by Gilbert’s lateral approach [27]. To preserve knee and ankle stability, respectively, a bone length of 8 cm proximal to the harvest site and a distal bone length of 6–8 cm of distal to the harvest site were left in situ. When an osseo-cutaneous free flap was harvested, a muscle cuff with parts of soleus and flexor hallucis longus muscle was included to protect the perforators. Before donor-site wounds were closed, a vacuum drainage (Redon) was installed. Wound closure at the lower limb was performed using a split skin graft over the harvested skin flap or primarily in all cases of sole bone flaps without skin paddles.
Examples for the clinical course of a subtotal bone graft loss (PFF) were illustrated in Figure 3, Figure 4 and Figure 5 and an example of TFF is demonstrated in Figure 6.
2.2. Study Parameters and Evaluator Calibration
The following parameters were collected: Patient age at the time of flap transfer, sex, primary diagnosis, planning procedure, location, type of defect classified according to Brown et al. [29,30], number of fibula segments, reconstruction time (immediately vs. delayed), flap condition, part of flap loss, and reason for flap loss. Patients’ medical records were analyzed independently for flap outcomes.
2.3. Inclusion and Exclusion Criteria for Study Subjects
In this study, we enrolled all patients who underwent a reconstruction of the maxilla or mandible (immediately or delayed) with a FFF. Only cases with incomplete data sets and/or medical records were excluded (n = 2).
2.4. Statistical Analyses
Fischer test and Freeman–Halton extension [31] were used to compare flap outcome with sex, ASA-Score, alcohol and tobacco abuse, time and method of reconstruction, and the number of fibular bone segments. Students t-test was performed to compare the mean age at FFF-transfer, operating time, duration in the ICU, and time of hospitalization between the three flap outcome groups after verification of normality. p < 0.05 was defined as statistically significant. The statistical analysis was carried out with SPSS 25 (SPSS Inc., Chicago, IL, USA).
2.5. Ethics Statement/Confirmation of Patients’ Permission
The study was approved by the local Ethics Committee of the Justus-Liebig University Giessen (AZ35/20) and patients’ consent was not necessary for this retrospective study. The patients consented that their intraoral pictures and X-ray images may be used anonymously in the publication. All data in the Microsoft Excel spreadsheet were pseudonymized.
3. Results
A total of 180 fibula free flaps (FFF) were performed over a period from January 2002 to June 2020. Complete flap success was recorded in 144 cases (80.0%). The remaining 36 flap failures were categorized into the two major groups partial (PFF) and total flap failure (TFF). PFF occurred in n = 16 (44.4%) and TFF in n = 20 (56.6%) cases (Table 1). No statistically significant difference concerning the age at flap transfer, sex, time, and method of reconstruction was apparent. Furthermore, no significant differences were detected in relation to surgical parameters (neck dissection, tracheostomy, radiation therapy) and general risk factors (alcohol and tobacco abuse). There is a significant difference concerning the duration of hospitalization between the groups PFF (mean 22.6 ± 9.7 days) and TFF (mean 33.8 ± 18.8 days) (p = 0.038). No statistically significant differences concerning operating time and duration in the ICU between PFF and TFF were detected.
While TFF occurred in a median 8.5 days, PFF was clinically incident later. All TFF were an early complication. Out of 20 TFF (100%), four arterial and four venous thrombosis were found during anastomosis revision. The aetiology of the flap failure of the remaining 12 cases (60%) are unknown. PFF of the skin paddle (n = 11) was observed in a median time of 22.5 days and therefore considered as a late complication. The onset of PFF of bone segments without skin paddles (n = 4) was detected much later at a median time of 101.5 days.
PFF was analyzed in detail. After maxillary reconstruction, two partial and three total flap failures were found in the investigation. This corresponds to 13.5% (n = 5) of the study collective. Two cases of PFF of the skin paddle was found after maxilla reconstructions (Brown Class II and III) with uni-segmental fibular, and three TFF were observed in uni- (n = 2) and bi-segmental reconstruction (n = 1).
In mandible reconstruction, PFF was observed in 87.5% of cases. A total number of 14 partial flap failures—nine losses of the skin paddle, four isolated bone graft losses, and one combination of both—were found in mandible reconstructions after tumor recurrence (Table 2). Out of 11 skin paddle losses (PFF), 81.81% (n = 9) occurred in the conventional non-VSP group.
TFF was observed mostly in Brown class I (n = 7) and II (n = 6) defects. Subtotal loss of the skin paddle was incident in 68.7% of cases (n = 11 out of 16). Isolated loss of fibular bone segments was found in 25.0% (n = 4) and a combination of both was reported in only one case (6.3%). PFF was found in 50.0% (8 out of 16 cases) of uni-segmental, 25.0% (n = 4) of bi-segmental, and 25.0% (n = 4) of tri-segmental jaw reconstructions. A total flap loss occurred in 55.0% of cases after bi-segmental and in 40.0% of cases after uni-segmental reconstructions (Figure 7). There was a non-significant trend towards TFF in poly-segmental reconstructions (p = 0.114).
A total loss of the skin paddle (n = 11) was observed at a mean of 27 days (median 22 days, range 2–67 days) and an isolated loss of bone graft segments at 181 days (n = 4; median: 101.5 days, range 37–499 days) post surgery. Kaplan–Meier survival function was calculated and visualizes the different periods of partial soft and hard tissue failure (Figure 8).
In comparison to the beginning of radiation therapy in the complete success group (n = 40, mean 52.9 days, median 49 days, range 21–98 days), PFF of the skin paddle generates a delay (Figure 9). Radiation therapy started at a mean of 63.5 days (n = 4, median 50.5 days, range 39–114 days). The difference remains without any statistical significance (p = 0.358).
Clinical flap necrosis and time of bone graft removal were compared with the number of bone segments used. Statistical analysis showed no significant differences between the uni- and bi-segmental graft losses. Overall, clinical flap loss was observed at a mean of 12 days after surgery (Median 8.5 days, range 0–40 days) and surgical removal of the avital grafts at a mean of 86.4 postoperative days (Median 22.5 days, range 2–503 days) (Figure 10).
Comparing TFF after maxillary and mandibular reconstruction, it is noticeable that maxillary TFF cases were a mean of 73.3 years old, and thus older than mandibular TFF cases (62.5 years). Therefore, with unequal variance, there is a statistically highly significant difference, which can be explained by the composition of the collective (p < 0.001). Regarding the first clinical sign of impending TFF, signs of TFF were documented after 3.3 days in the upper jaw and after 14.4 days in the lower jaw (Table 3). This observation is statistically significant (p = 0.007). Concerning further surgical procedure and removal of the necrotic graft, no statistically significant difference between maxilla and mandible was observed (Figure 11).
4. Discussion
4.1. Rate of PFF and TFF
Thrombosis, kinking, and spasm of the vessels have been reported as common causes of total free-flap failure in the early phase after microvascular anastomosis [32]. Venous thrombosis is more common than arterial thrombosis due to the low-flow and low-pressure venous system. Unrecognized venous thrombosis can lead to backward perfusion failure up to total stasis in the arterial system. This is followed by flap ischemia, no-reflow, and subsequent flap loss [33,34]. Fibular flaps are reported with success rates of up to 95.0% [7,14,15,16]. Study findings have shown a cumulative success rate of 88.9% (80.0% complete success and 8.9% partial flap failure). The total failure rate in the presented study is 11.1% over the last 19 years and over all types of indications for reconstruction, time of reconstruction, and method of planning (Non-VSP vs. VSP). In comparison to the here reported investigations, other reconstructive centers report total fibular flap failure rates of up to 12.4% (Table 4). Comparability of the results must be ensured concerning the chosen definition of flap success and PFF/TFF. In the presented study, strict criteria for PFF and TFF was defined. Only clear definitions will engage the collection of comparable data. Retrospective study design without standardization is often of poor data quality due to incomplete follow up data and different investigators. However, data collection over 19 years by a single investigator appears to be impractical. Loss and removal of the whole graft are clear parameters for TFF. From the clinical course and as a result of perfusion disorder through its vascular pedicle, TFF is an early flap failure. Therefore, minor, insufficient perfusion of flap elements leads to malnutrition, and thus to consecutive (sub-)total loss of skin paddle and/or bone segments. This was defined as PFF. PFF therefore does include the functional use of the flap and appears as a late flap failure. Most published data lack a differentiation between soft and hard tissue loss. Partial flap failure was reported with an incidence of 3–14% but has not been further differentiated in most cases (Table 4).
A retrospective single-center study on 129 FFF transfers over the last 20 years found TFF in 12.4% and PFF in 7.8% of cases [21]. An investigation on 20 virtual planned FFF showed that preoperative planning based on preoperative CT-scan allows to include the preoperatively planned skin paddle area [13]. Another clinical trial included preoperatively marked perforator vessels for skin paddle in digital planning and noted a survival rate of 92% (n = 24) in FFF transfer with three total and two partial skin paddle losses [12]. Other investigators observed seven total flap losses and three losses of skin paddle in a total of 99 FFFs [16].
In the present study, there were four losses of fibular bone segments and only two of them occurred after radiation therapy (RT). Loss of the skin paddle occurred in two cases of maxillary reconstruction and in nine cases of uni- and poly-segmental reconstruction of the mandible. After an average time of 27 days (median: 22 days, range 2–67 days), partial loss of the skin paddle was observed whereas partial bone loss occurred after mean 181 days (Median: 101.5 days, range 37–499 days). Swelling and edema are results of ongoing inflammatory processes and wound healing immediately after surgery. A critically reduced perfusion of the septo-cutaneous perforators could be the consequence. Its maximum dimension can be expected 2–3 days after surgery. The unusually late appearance of visible (sub-)total dysfunction of the skin paddle perfusion after more than the median time of 3 weeks should be interpreted with caution and as result of documentation bias. Any influence of RT in this respect can be excluded, since RT always started after PFF was already observed. The onset of adjuvant RT in the group PFF skin was at median 50.5 days (range 39–114 days) after surgery in comparison to the control group comprising complete flap success (n = 40), in which RT began in median 49 days (range 21–98 days) after surgery. A statistically significant difference could not be observed. However, an adjuvant RT for oncologic reasons was not to be delayed by a PFF. The results must be interpreted with caution due to the small number of cases. In the literature, the effect of prior irradiation on partial or complete loss of FFF compared with unirradiated grafts has often been reported to be statistically insignificant [38,39,40,41,42]. The effect of postoperative irradiation on partial flap failure in microvascular head and neck reconstruction has not been well described in literature and indicates that further studies are needed in this area. Verhelst et al. focused on perioperative irradiation but it was not identified as a statistically insignificant risk factor for flap failure [21]. In a study by He et al., 9 of 17 patients were irradiated postoperatively and all grafts sustained [43]. In this study, no cases of PFF were detected during or after RF. Under RT conditions, PFF could be similar to radiogenic oral mucositis, which is associated with an early inflammatory response [44,45]. These factors provide a target for biology-based mucositis-prevention strategies [46,47], and thus for PFF prevention. Further, the option of an additional skin paddle for defect closure after oncologic resection is without doubt one of the major advantages of the FFF in addition to its clinical and technical function of flap monitoring. On the other site, wound healing disorder of the donor site after skin paddle harvesting appears at a rate of 1.07–31.2% [23,48,49]. In literature, different techniques for closure of the donor site have been described [50]. Focused only on monitor function, the price for an unreliable monitor skin paddle seems to be high and should be critically reflected. Nevertheless, some authors believe that the reliability of the skin paddle for the closure of recipient site defects is insufficient in non-irradiated [51] and especially in irradiated patients [52]. In a retrospective investigation, Thome et al. observed 20% of skin paddle failures (n = 27) and came to a similar conclusion [53]. Other authors found a stable and sufficient vascular supply of the septo-cutaneous skin paddle by the septum intermusculare posterius and perforator vessels around the musculus soleus [54,55,56]. They emphasize the necessity of a muscle cuff around the posterior septum, which contains vessels that are crucial for skin paddle survival [24].
Partial bone loss may occur more frequently than previously observed and described in the literature as a result of malnutrition. Sufficient neovascularization to allow free-flap survival independent of the vascular pedicle has been reported to occur within 7 to 10 days in myo-cutaneous flaps [57,58,59]. In contrast, a comparative prospective clinical study measured hemoglobin oxygenation and capillary flow in 50 flaps (25 forearm flaps, 15 osseo-cutaneous fibular flaps, and 10 anterolateral thigh flaps) at 4 and 12 postoperative weeks. The authors found that flap autonomization rates were significantly higher in the lower jaw and non-irradiated defect sites. In addition, fascio-cutaneous flaps were found to be autonomized faster than osseo-myo-cutaneous free flaps. Myo-cutaneous flaps were never found to be autonomized after 4 weeks [60]. Kumar et al. studied blood supply of fascio-septo-cutaneous free flaps several months after surgery and found no significant blood flow through vessels across the flap inset [59]. Mücke et al. found that osseo-myo-cutaneous free flaps are significantly dependent on vascularity of the original anastomoses even 1 year after surgery [60]. According to their data, our findings should be interpreted as an adverse effect of radiation therapy (n = 2) and two “real” partial bone segment failures. The risk to develop osteoradionecrosis is decreased in patients with high body mass indices and on steroid therapy [61] through adequate soft-tissue bulk paired with the high-quality vascularized fibula bone [62]. Data published in the literature show that osteoradionecrosis of the original mandible occurred after a median time of 10.9 months (range 1.8–89.7 months) after RT and 90% occurred within 37.4 months [63]. In contrast, our data show bone loss after a median time of 3.38 months (range 1.23–16.63 months) and more than 6 months earlier. This observation should be interpreted with caution due to the low number of cases and should be further studied in larger study groups.
Early TFF was incident in n = 3 maxillary and n = 17 mandible reconstructions. TFF was found after mandible reconstruction in anterior defects (Classes III-IV, 3 out of 17 cases, 17.6%) and more frequently in lateral defects (Classes I–II, n = 14, 82.4%). Uni- and bi-segmental were commonly used for these Classes I–II reconstructions. Reasons for increased TFF in class I and II were critical pedicle course (inner surface of mandible and mouth floor), kinking of the vascular bundle [64] and length [21,65,66]. In addition to known general risk and complicating factors, further risk factors for flap failure include postoperative swelling and edema, hematoma, movement of the neck, circular tracheal tube fixation loop, and course of the vessel through the neck [33].
The therapeutic procedure for partial skin or isolated bone loss depends on the jaw affected. If PFF of the skin paddle occurs in the maxilla, it is usually an uncritical situation and wound healing from peri-osseous tissue can be expected. When bone loss in the maxilla occurs, a “simple” prosthetic rehabilitation by obturator prosthetic is a therapeutic alternative [67,68] if another microvascular bone graft is not desired. Large defects can be downsized with local tissue advancement. Functional impairment (eg. scars) might be addressed in a two-staged procedure. Safe flaps routinely used in our department are the temporal myo-fascial [69], pectoralis major [70,71], and deltopectoral flaps [72].
In the mandible, skin paddle loss is often noncritical when the primary bone graft is vital. After wound healing local flaps and staged scars, loosing procedures can be necessary to improve dysfunction such as trismus [73]. Flaps of choice in this situation are often radial forearm [74], pectoralis major [70,71], and deltopectoral flaps [72]. When PFF of bone segments or TFF after mandible reconstructions appear, there are different strategies available that need to be evaluated in light of the patient’s condition. If patient’s condition is poor and the avital graft showed no signs of inflammation, it was left in the oral cavity (Figure 6). If inflammation and/or loosening of osteosynthesis material occurred around the avital segment, removal is necessary. Sometimes further use of osteosynthesis is possible, especially if patient-specific osteosynthesis was used. However, in the majority of cases, removal of the osteosynthesis will become necessary (Table 3). Re-osteosyntheses could be useful in combination with distant flaps like pectoralis major flaps, deltopectoral flaps, and bone hip grafts. The staged procedure of second attempts microvascular bone graft is possible after critical evaluation. The removal of the avital graft and the anticipation of stable scars building and “functional” pseudarthrosis is a further option (Figure 6).
4.2. Influence of Age at Flap Transfer, BMI, ASA-Score and Risk Factors in Terms of Flap Success in Relation to PFF and TFF
In this study, no significant differences between patients’ age at flap transfer and flap outcome were observed. This confirms other investigations that patients’ age at flap transfer is not crucial for flap success [75,76]. It is a surrogate parameter for the general condition of the patient [77,78]. A prospective study on 215 patients found that age ≥ 70 years had a significantly higher ASA-Score and shorter duration of surgery. Age was a risk factor for longer ICU stay and complication rate. They found no influence of age on the length of hospital stay and overall success of microvascular reconstructions [79]. In this study, more than 92% were rated ASA 2 or 3. All partial flap failures and all but one total flap occurred in both groups. ASA score and duration of the operation were found to be independent risk factors for operative revisions [76]. In literature, ASA-Rating is correlated with a higher number of postoperative complications after microvascular reconstructions [80,81] and the overall survival [82]. We calculated the relation between ‘Age at flap transfer’ and BMI and found an evenly distributed pattern.
Concerning alcohol and tobacco abuse in the investigated group, no statistically significant differences were found. In published literature, alcohol abuse was identified as a risk factor for postoperative adverse events [82]. Tobacco abuse was shown to reduce overall survival time compared with non- and never-smokers [83,84]. A review by Van Imhoff et al. stated that survival rates are lower and recurrence rates are higher in patients who continued to smoke after having being diagnosed with Head and Neck SCC in comparison to patients who stopped smoking [85].
BMI had no statistically significant influence on flap success in this study. Low BMI or underweight at diagnosis was an independent, unfavorable prognostic factor [86,87]. Obesity was associated with better outcome and was not an independent risk factor for postoperative complications of free tissue transfer [88,89]. Other investigators found that higher BMI/obesity is a risk factor for peri- and postoperative medical complications [90].
The duration of hospitalization was calculated with a mean of 22.6 days in the PFF group and a mean of 33.8 days in the TFF group. Statistically significant differences (p = 0.038) were found in the occurrence of partial or total flap failures (Table 1). While the majority (68.75%, n= 11 out of 16) of all partial flap failures are a dysfunction of the skin paddle failures (mean duration of hospitalization partial flap loss group 20.71 days), we conclude that loss of that skin loss does not result in significantly longer hospital stay than in total flap losses. Stepwise removing of avital flap parts, deperiostizing of the bone graft, and covering with oral mucosa is an attempt for flap salvage. However, the initial stay at the ICU seems to have no statistical influence concerning upcoming PFF or TFF. It was calculated in both groups with a mean of approximately 2.0 days.
No statistically significant difference concerning mean operating time (PFF: meantime 546 min, TFF: meantime 524 min) and flap outcome was found. Surgery time is described as a risk factor for postoperative complications [91,92,93]. Increased operating time may also be the result of a younger surgeon learning and being taught by an older instructing surgeon. However, operating time should be reduced whenever possible [92]. The study could not include ischemia time in the risk analysis because this parameter was not recorded or was incomplete.
4.3. PFF and TFF in Non-VSP vs. VSP and Reconstruction Methods (Immediate vs. Delayed)
The majority of isolated skin paddle losses occurred in the non-VSP group. Reasons can be seen in mechanical trauma and manipulation during free-hand transplant forming i.e., preparation of bone segments and revised application of osteosynthesis. Individually custom-made cutting guides stabilize and preserve intersegmental connectors for stabilization of several bone segments, which provide a valuable support on the vascular pedicle during transplant preparation and shaping.
No statistically significant differences were found concerning patients’ preoperative planning procedure (non-VSP vs. VSP) and time of reconstruction (immediately vs. delayed). The results confirmed the findings of other clinical investigations [94]. A retrospective study of 128 osseous free flaps with a minimum follow-up of 12 months evaluated plate-related complications in patient-specific versus conventional fixation systems. They found more complications with patient-specific plates (e.g., wound healing disorders, plate exposure, fixation failure, and subtotal osseous union) in comparison to conventional reconstruction plates, but the differences were statistically insignificant.
One possible reason for (sub-)total bone loss despite maintained perfusion of the vascular pedicle might be trauma during preparation, segmentation, and shaping of the fibula graft. Preoperatively planned and fabricated saw guides and patient-specific implants ease and accelerate the surgical procedure itself, which should be helpful in avoiding mistakes and facilitating the handling of the fibula graft. More complex shaping and osteotomization of bone segments leads to manipulation of the vascular pedicle during dissection and puts it at risk [22]. Furthermore, the impact of VSP and patient-specific plates in terms of wound healing abnormalities, plate exposure, and subtotal osseous union shows a trend towards increased complication rates compared with non-VSP with hand-bended plates. Plate-related complications were increased with radiotherapy and multi-segment flaps [95].
Further investigations on partial flap loss of osseomyocutaneous FFF are needed.
5. Conclusions
The fibula free flap constitutes a standard therapy for jaw reconstructive surgery. The present results of 180 fibula free flap over a period of 19 years shows a cumulative success rate of 88.9%, which is well comparable with other studies. The findings of our long term monocenter retrospective investigation are a position statement about flap success and partial and total loss rates, which was achieved by careful patient selection and a two team approach to reduce operating time. In partial or total flap failure, no statistically significant correlation was observed between patient age, sex, ASA, BMI, alcohol and tobacco abuse, time, and method of reconstruction (virtual versus non-virtual surgical planning). Total flap failure caused significantly prolonged hospitalization time. Partial flap failure affected mainly the skin paddle. Two-thirds of these cases were found in the non-VSP group and only two cases were observed in the virtual surgical planning group. This could be attributed to protective effects of the cutting-guide template, which possibly decrease the mechanical trauma during surgery.
Acknowledgments
The authors are grateful for the consent of the patient for presented X-rays and clinical images. This publication is part of the second author’s dental doctoral thesis (SS).
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Author Contributions
Conceptualization, M.K.; methodology, S.S., M.K., C.B.; formal analysis, M.K.; investigation, M.K., and S.S; data curation, M.K. and S.S.; writing—original draft preparation, M.K., S.S., S.A. and S.B.; writing—review and editing, M.K., S.S., S.A., C.B., D.S., H.-P.H. and S.B.; visualization, M.K., D.S., H.-P.H. and S.A.; supervision, M.K., H.-P.H., S.B. and S.A.; project administration, M.K. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Justus-Liebig University Giessen (AZ35/20, approval 25.5.2020).
Informed Consent Statement
Patient consent was waived as the study is a retrospective data analysis.
Data Availability Statement
The data presented in this study are available upon request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Schematic illustration of reconstructive workflow and stratification in partial and total flap failure groups. The major characteristic of PFF is the remaining blood supply by the vascular pedicle. In contrast to this, TFF is characterized by interrupted graft perfusion.
Figure 2 Example of ‘PFF skin’ after maxilla reconstruction.
Figure 3 The clinical course of PFF. (OPT 1) Due to the recurrence of an ossifying fibroma (odontogenic tumor) in the ramus ascendens mandibulae in a 22-year-old patient, (OPT 2) a continuity resection and simultaneous reconstruction with a bi-segmental fibula and CAD/CAM plate was planned. (OPT 3) The clinical submandibular fistula had a connection to the plate (Figure 4A). (OPT 4) An OPT image was obtained after removal of the avital fibular segments and re-stabilization of the remaining graft. There is initial evidence of incipient bone healing on the proximal resection-site. (OPT 5) Follow-up visit at 9 weeks after re-stabilization. In the condylar segment, bone healing is pictured, and at the distal segment, progressive resorption is visible. (OPT 6) Progressive bone healing and callus formation originating from the resection site is visible 19 weeks after re-stabilization.
Figure 4 (A) Clinical aspect 4 weeks after reconstruction. After reopening the submandibular approach and excision of the skin fistula, there was no evidence of screw loosening. Temporary unscrewing of the screw (No. 5) leads to bleeding. (B) With a new fistula, the site was reentered 8 weeks after surgery and the screw was removed again. There was no clear bleeding from the screw hole. In addition, the anterior-caudal edge of the bone was removed.
Figure 5 (C1) The CAD/CAM plate was removed 14 weeks after surgery when the fistula was productive again. (C1–C3) A sharp demarcation line caudal to the crestal edge of the plate became visible and was conspicuous. (C2) Between the fibula segments, an incipient ossification of the gap was observed. The underlying bone was pale. (C3) The bone was removed caudally. The bone marrow was replaced by granulation tissue and was removed. (C4) The intersegmental ossification was not yet sufficient so that stabilization again was necessary.
Figure 6 The following OPTs outline the clinical course of TFF in a 76-year-old patient in good general condition who suffered from osseous metastasis of prostate cancer and underwent FFF. (OPT 1) A pathologic fracture occurred after the removal of necrotic bone in the right lower jaw in the setting of bisphosphonate induced MRONJ stage III (treatment with Zoledronacid/Denosumab in prostate cancer) [28]. (OPT 2) Virtual planning of double-barrel fibula was performed. CAD/CAM plate was used for stabilization and the simultaneous insertion of two dental implants was performed. (OPT 3) At 3 weeks post-surgery, the skin paddle was lost. A surgical exploration ended with the removal of an avital distal graft segment and modification of the plate in situ. The vascular pedicle of the remaining FFF still rendered a clear signal in the Doppler ultrasonic probe. (OPT 4) At 16 weeks after surgery, the remaining graft segment also had to be removed in the setting of continued inflammation and the absence of a Doppler signal. (OPT 5) At 22 weeks after surgery: The screws loosened in the anterior mandible segment so that the remaining plate with teeth 32–42 and a bone sequester had to be taken out.
Figure 7 Partial or total flap failure in relation to the number of fibula segments (p = 0.114).
Figure 8 Kaplan–Meier function was drawn for the three sub-groups of PFF. The abscissa axis “time” (days) is drawn on a logarithmic scale.
Figure 9 Comparison of the onset of adjuvant radiation therapy between the groups of complete flap success (n = 40) and PFF skin (n = 4).
Figure 10 TFF concerning the first clinical signs of flap necrosis and time of removal of the avital graft was visualized by Kaplan–Meier function. The abscissa axis “time” (days) is drawn on a logarithmic scale.
Figure 11 TFF analysis. Clinically diagnosed flap necrosis and further surgical interventions (removal of graft) are shown according to jaw location (maxilla or mandible) in the postoperative time course. The ordinate axis “time” (days) is drawn on a logarithmic scale.
cancers-13-00865-t001_Table 1Table 1 Clinical details of partial (PFF; n = 16) and total flap failures (TFF; n = 20) after jaw reconstruction with fibular free flaps.
N = 36 PFF
N = 16 (44.4%) TFF
N = 20 (56.6%) p-Value
Age (years), SD 59.9 ± 14.4 62.5 ± 9.5 p = 0.520
Follow-up (months), SD 48 ± 42.9 31.5 ± 31.6 p = 0.193
Type of flap loss
PFF, Skin paddle 11
PFF, Bone segment 4
PFF, Both 1
Total flap loss (TFF)
20
Sex
Female 5 6 p = 0.609
Male 11 14
Diagnosis
Benign tumor
Malignant tumor
MRONJ
ORN 1
15
15
2
3
Reconstruction
Immediate 14 17 p = 0.610
Delayed 2 3
Reconstruction
Non-VSP 10 10 p = 0.341
VSP 6 10
Neck dissection
Unilateral 11 13 n.s.
Bilateral 3 3
None 2 4
Tracheostomy
None 6 8 n.s.
Primary 9 11
Secondary 1 1
Irradiation
Preoperative 1 3 n.s.
Postoperative 8 4
None 7 13
Risk factors
Alcohol abuse 5 9 p = 0.348
Tobacco abuse 9 13 p = 0.546
Operating time (min) 546.2 ± 94.9 524.4 ± 97.2 p = 0.504
Duration ICU (days) 2 ± 1.3 2.1 ± 1.7 p = 0.847
Hospitalization (days) 22.6 ± 9.7 33.8 ± 18.8 p = 0.038
BMI
≤18
18 ≤ 25
25 ≤ 30
30 ≤ 35
>35
9
3
4
1
9
7
2
1
ASA-Score
ASA 2 10 7
ASA 3 6 12
ASA 4
1
n.s. = not significant; ORN, Osteoradionecrosis; MRONJ, Medication-related osteonecrosis of the jaw; VSP, virtual surgical planning; BMI, Body mass index; SD, standard deviation.
cancers-13-00865-t002_Table 2Table 2 Table depicting the locations according to the classification by Brown et al. where PFF (n=16) and TFF (n=20) occurred [29,30].
Type of Defect PFF Skin (n = 11) PFF Bone (n = 4) PFF Both (n = 1) TFF (n = 20)
Maxilla
II 1 - - 2
III 1 - - 1
Mandible
I
4
-
1
7
Ic - - -
1
II
2
2
-
6
IIc - 1 - -
III
3
1
- 2
IV - - -
1
cancers-13-00865-t003_Table 3Table 3 Clinical details of total flap failures (n = 20).
N = 20 Maxilla (n = 3) Mandible (n = 17) Overall (n = 20)
p
Age (years), SD 73.3 ± 1.8 60.6 ± 8.9 62.5 ± 9.5 p = 0.001 ^
Follow-up (months), SD 10.3 ± 9.7 35.2 ± 32.8 31 ± 31.6
The earliest sign of flap dysfunction (days) 3. 3 ± 3.5
(Median 3) 14.4 ± 11.1
(Median 10) 12 ± 10.9
(Median 8.5) p = 0.007 ^
Surgical validation and avital flap treatment procedure (days) 54 ± 60.1
(Median 36) 92.1 ± 132.0
(Median 21) 86.5 ± 123.6
(Median 22.5) p = 0.449 ^
Anastomosis revisions 2 6 8
Arterial thrombosis ‡ 2 2 4
Venous thrombosis ‡ - 4 4 n.s
Unknown 1 11 12
Explantation of bone graft 2 16 18
Osteosynthesis (PSI) removal 1 11 12
Re-osteosynthesis - 3 3
Second flap 1 8 9
Temporalis muscle flap 1 1 2
Deltopectoral flap - 1 1
Pectoralis major flap - 2 2
RFF - 1 1
FFF - 2 2
Hip graft (non-DCIA) - 1 1
‡ Kind of thrombosis was evaluated during microsurgical revision. (n.s. = not significant; ^ Equal variances not assumed; DCIA, deep circumflexia iliac artery; PSI, patient-specific implant; SD, standard deviation; RFF, radial forearm flap).
cancers-13-00865-t004_Table 4Table 4 Overview of FFF total and partial flap failure rates in the literature.
Authors Investigation Period
n
Total Flap Failure Partial Flap Failure
This study 2002–2020 180 11.1% 8.9%
Colletti et al. [16] 2002–2010 99 7% 3%
Gallegos-Hernandez et al. [35] 1996–2006 87 16.1% -
Götze et al. [12] 2013–2015 24 12.5% 8.3%
Lopez-Arcas et al. [36] 1992–2006 117 - 8.5%
Momoh et al. [23] 2005–2009 157 1% 14%
Mücke et al. [37] 2009–2013 76 9.2% -
Seruya et al. [22] 2003–2012 68 4.41% 11.76%
Shroff et al. [14] 2009–2013 30 6.66% -
Verhelst et al. [21] 1996–2016 129 12.4% 7.8% | Recovering | ReactionOutcome | CC BY | 33670721 | 19,661,708 | 2021-02-18 |
What was the outcome of reaction 'Pathological fracture'? | Partial and Total Flap Failure after Fibula Free Flap in Head and Neck Reconstructive Surgery: Retrospective Analysis of 180 Flaps over 19 Years.
Fibula free flap (FFF) is widely used in head and neck reconstructive surgery and is considered as a standard and therapy of choice after ablative cancer surgery. The aim of this retrospective monocenter study was to determine the success rates of fibula free flaps for jaw reconstruction after ablative tumor surgery. The disease course of patients who underwent jaw reconstructive surgery with FFF from January 2002 to June 2020 was evaluated regarding the flap success rate. Flap failure was analyzed in detail and categorized into two groups: partial flap failure (PFF) and total flap failure (TFF). A total of 180 free fibular flaps were performed over the last 19 years and a total of 36 flap failures were recorded. TFF occurred in n = 20 (56.6%) and PFF in n = 16 cases (44.4%) cases. No statistically significant differences were found concerning patients' age at flap transfer, sex, BMI, ASA-Score, preoperative non-virtual or virtual surgical planning (non-VSP vs. VSP), and time of reconstruction (immediately vs. delayed). Duration of hospitalization shows statistically significant differences between both groups (p = 0.038), but no differences concerning operating time and duration on Intensive Care Unit (ICU). Partial flap failure appears to be underreported in literature. Sub- and complete failure of the skin paddle leads to clinical complaints like uncovered bone segments and plate exposure. Partial or complete FFF failure lead to infections on the recipient site and prolonged wound healing and therefore may cause a delay of the beginning of adjuvant radiation therapy (RT). PFF of hard tissue can be induced by RT.
1. Introduction
Since the first mandibular reconstruction with a fibula free flap (FFF) by Hidalgo in 1989, it has been shown that FFF is a reliable and versatile graft [1,2]. Currently, FFF is considered as standard therapy in head and neck reconstructive surgery, providing the optimal precondition for dental implant success and therefore for oral and dental rehabilitation [3,4]. Long-term complications on the donor-site are relatively low. Most patients have been satisfied with the functional and aesthetic results [5,6]. The number of free tissue transfers of soft and/or bone tissue defects have increased significantly in recent years [7]. The flap provides the opportunity to include a septo-cutaneous skin paddle of up to 200 cm2. Cadaver studies investigating skin perfusion through selective injection have shown that a skin area of 12 × 7 cm can be perfused by a single perforating vessel [8]. A recent milestone in operative techniques is the possibility of computer-assisted surgery (CAS) and virtual surgical planning (VSP) in reconstructions of jaws [9,10,11]. VSP initially focused on bone grafts. The innovative potential lies in the design of a cutting guide that takes into account the course of the cutaneous perforating vessels based on preoperative CT and sonographic measurements [12,13]. For skin paddle harvesting, the support of perforator vessels is crucial. Fibular flaps have been reported to allow a success rate of up to 95% [7,14,15,16]. The causes of flap failure are anastomosis insufficiency, more frequent venous congestion (e.g., edema, hematoma), rare arterial occlusion (e.g., embolism, thrombus, kinking), vasospasms, postoperative bleeding, and coagulopathies [17,18,19,20].
However, detailed data about partial FFF loss are rare and seem to be underreported in literature. An analysis of risk factors for flap failure and complications in a low-level center of 129 FFFs over a time span of 20 years reported a PFF rate of 7.8%. By definition, (sub-)total flap loss describes the failure of the skin paddle and/or the loss of one or more bone graft segments in poly-segmental reconstructions [21]. The data published to date lack a differentiation concerning soft and/or hard tissue loss. A comparative investigation on computer-assisted versus conventional FFF technique for craniofacial reconstruction found six skin paddle and two segmental graft failures, which corresponded to a PFF rate of 11.76% (n = 8 out of 68) and a TFF rate of 4.41% (n = 3) [22]. Comparative results of partial loss were reported with a range of 3–14% [16,23]. This should be considered when the often-described advantage of the skin paddle as a vital monitor is advocated [24,25]. Gennaro et al. mentioned that a thin muscle cuff around bone, e.g., the fibula or vascularized iliac crest bone flap, is needed for flap harvesting. In these cases, a direct clinical assessment even without the use of a Doppler probe is advisable [26]. However, if PFF or TFF occurs, therapeutic options and decisions must be made to reduce local infection, functional impairment, and increase the patient’s quality of life. In this study, we have assessed and discussed the therapeutic options in the setting of TFF.
The aims of this study are:to estimate the rate of partial flap loss ((sub-)total loss of skin paddle and/or failure of graft segments) and total flap failure over a long time period of 19 years, and to suggest further therapy procedures according to localization and defect type;
to examine a correlation between age at flap transfer, BMI, ASA-Score, and risk factors in terms of partial and total flap failure; and
to investigate whether there is a correlation between non-VSP vs. VSP and time of reconstruction (immediate vs. delayed).
2. Materials and Methods
2.1. Study Design and Patient Population
The study was conducted as a monocentric, retrospective study. Medical records of all patients who underwent FFF in the head and neck region from January 2002 to June 2020 were analyzed in respect of success of the flap transfer procedure. Flap failure was stratified into two groups: partial flap failure (PFF) and total flap failure (TFF) (Figure 1). PFF was defined as any loss of parts of the skin paddle (Skin) (Figure 2), parts or segments (poly-segmental reconstruction) of bone grafts (Bone) (Figure 3), or a combination of both (Both). The major characteristic of PFF is the remaining blood supply by the vascular pedicle. In contrast to PFF, TFF is characterized by discontinued perfusion of the graft (i.e., thrombosis). Intra- or extraoral wound dehiscences around the skin paddle alone did not match the criteria for PFF and were not included.
All patients underwent a preoperative CT or MRI angiography to ensure the presence of a three fibular vessel anatomy and the absence of significant arteriosclerotic changes in the lower leg. Free fibula flap dissection was performed by Gilbert’s lateral approach [27]. To preserve knee and ankle stability, respectively, a bone length of 8 cm proximal to the harvest site and a distal bone length of 6–8 cm of distal to the harvest site were left in situ. When an osseo-cutaneous free flap was harvested, a muscle cuff with parts of soleus and flexor hallucis longus muscle was included to protect the perforators. Before donor-site wounds were closed, a vacuum drainage (Redon) was installed. Wound closure at the lower limb was performed using a split skin graft over the harvested skin flap or primarily in all cases of sole bone flaps without skin paddles.
Examples for the clinical course of a subtotal bone graft loss (PFF) were illustrated in Figure 3, Figure 4 and Figure 5 and an example of TFF is demonstrated in Figure 6.
2.2. Study Parameters and Evaluator Calibration
The following parameters were collected: Patient age at the time of flap transfer, sex, primary diagnosis, planning procedure, location, type of defect classified according to Brown et al. [29,30], number of fibula segments, reconstruction time (immediately vs. delayed), flap condition, part of flap loss, and reason for flap loss. Patients’ medical records were analyzed independently for flap outcomes.
2.3. Inclusion and Exclusion Criteria for Study Subjects
In this study, we enrolled all patients who underwent a reconstruction of the maxilla or mandible (immediately or delayed) with a FFF. Only cases with incomplete data sets and/or medical records were excluded (n = 2).
2.4. Statistical Analyses
Fischer test and Freeman–Halton extension [31] were used to compare flap outcome with sex, ASA-Score, alcohol and tobacco abuse, time and method of reconstruction, and the number of fibular bone segments. Students t-test was performed to compare the mean age at FFF-transfer, operating time, duration in the ICU, and time of hospitalization between the three flap outcome groups after verification of normality. p < 0.05 was defined as statistically significant. The statistical analysis was carried out with SPSS 25 (SPSS Inc., Chicago, IL, USA).
2.5. Ethics Statement/Confirmation of Patients’ Permission
The study was approved by the local Ethics Committee of the Justus-Liebig University Giessen (AZ35/20) and patients’ consent was not necessary for this retrospective study. The patients consented that their intraoral pictures and X-ray images may be used anonymously in the publication. All data in the Microsoft Excel spreadsheet were pseudonymized.
3. Results
A total of 180 fibula free flaps (FFF) were performed over a period from January 2002 to June 2020. Complete flap success was recorded in 144 cases (80.0%). The remaining 36 flap failures were categorized into the two major groups partial (PFF) and total flap failure (TFF). PFF occurred in n = 16 (44.4%) and TFF in n = 20 (56.6%) cases (Table 1). No statistically significant difference concerning the age at flap transfer, sex, time, and method of reconstruction was apparent. Furthermore, no significant differences were detected in relation to surgical parameters (neck dissection, tracheostomy, radiation therapy) and general risk factors (alcohol and tobacco abuse). There is a significant difference concerning the duration of hospitalization between the groups PFF (mean 22.6 ± 9.7 days) and TFF (mean 33.8 ± 18.8 days) (p = 0.038). No statistically significant differences concerning operating time and duration in the ICU between PFF and TFF were detected.
While TFF occurred in a median 8.5 days, PFF was clinically incident later. All TFF were an early complication. Out of 20 TFF (100%), four arterial and four venous thrombosis were found during anastomosis revision. The aetiology of the flap failure of the remaining 12 cases (60%) are unknown. PFF of the skin paddle (n = 11) was observed in a median time of 22.5 days and therefore considered as a late complication. The onset of PFF of bone segments without skin paddles (n = 4) was detected much later at a median time of 101.5 days.
PFF was analyzed in detail. After maxillary reconstruction, two partial and three total flap failures were found in the investigation. This corresponds to 13.5% (n = 5) of the study collective. Two cases of PFF of the skin paddle was found after maxilla reconstructions (Brown Class II and III) with uni-segmental fibular, and three TFF were observed in uni- (n = 2) and bi-segmental reconstruction (n = 1).
In mandible reconstruction, PFF was observed in 87.5% of cases. A total number of 14 partial flap failures—nine losses of the skin paddle, four isolated bone graft losses, and one combination of both—were found in mandible reconstructions after tumor recurrence (Table 2). Out of 11 skin paddle losses (PFF), 81.81% (n = 9) occurred in the conventional non-VSP group.
TFF was observed mostly in Brown class I (n = 7) and II (n = 6) defects. Subtotal loss of the skin paddle was incident in 68.7% of cases (n = 11 out of 16). Isolated loss of fibular bone segments was found in 25.0% (n = 4) and a combination of both was reported in only one case (6.3%). PFF was found in 50.0% (8 out of 16 cases) of uni-segmental, 25.0% (n = 4) of bi-segmental, and 25.0% (n = 4) of tri-segmental jaw reconstructions. A total flap loss occurred in 55.0% of cases after bi-segmental and in 40.0% of cases after uni-segmental reconstructions (Figure 7). There was a non-significant trend towards TFF in poly-segmental reconstructions (p = 0.114).
A total loss of the skin paddle (n = 11) was observed at a mean of 27 days (median 22 days, range 2–67 days) and an isolated loss of bone graft segments at 181 days (n = 4; median: 101.5 days, range 37–499 days) post surgery. Kaplan–Meier survival function was calculated and visualizes the different periods of partial soft and hard tissue failure (Figure 8).
In comparison to the beginning of radiation therapy in the complete success group (n = 40, mean 52.9 days, median 49 days, range 21–98 days), PFF of the skin paddle generates a delay (Figure 9). Radiation therapy started at a mean of 63.5 days (n = 4, median 50.5 days, range 39–114 days). The difference remains without any statistical significance (p = 0.358).
Clinical flap necrosis and time of bone graft removal were compared with the number of bone segments used. Statistical analysis showed no significant differences between the uni- and bi-segmental graft losses. Overall, clinical flap loss was observed at a mean of 12 days after surgery (Median 8.5 days, range 0–40 days) and surgical removal of the avital grafts at a mean of 86.4 postoperative days (Median 22.5 days, range 2–503 days) (Figure 10).
Comparing TFF after maxillary and mandibular reconstruction, it is noticeable that maxillary TFF cases were a mean of 73.3 years old, and thus older than mandibular TFF cases (62.5 years). Therefore, with unequal variance, there is a statistically highly significant difference, which can be explained by the composition of the collective (p < 0.001). Regarding the first clinical sign of impending TFF, signs of TFF were documented after 3.3 days in the upper jaw and after 14.4 days in the lower jaw (Table 3). This observation is statistically significant (p = 0.007). Concerning further surgical procedure and removal of the necrotic graft, no statistically significant difference between maxilla and mandible was observed (Figure 11).
4. Discussion
4.1. Rate of PFF and TFF
Thrombosis, kinking, and spasm of the vessels have been reported as common causes of total free-flap failure in the early phase after microvascular anastomosis [32]. Venous thrombosis is more common than arterial thrombosis due to the low-flow and low-pressure venous system. Unrecognized venous thrombosis can lead to backward perfusion failure up to total stasis in the arterial system. This is followed by flap ischemia, no-reflow, and subsequent flap loss [33,34]. Fibular flaps are reported with success rates of up to 95.0% [7,14,15,16]. Study findings have shown a cumulative success rate of 88.9% (80.0% complete success and 8.9% partial flap failure). The total failure rate in the presented study is 11.1% over the last 19 years and over all types of indications for reconstruction, time of reconstruction, and method of planning (Non-VSP vs. VSP). In comparison to the here reported investigations, other reconstructive centers report total fibular flap failure rates of up to 12.4% (Table 4). Comparability of the results must be ensured concerning the chosen definition of flap success and PFF/TFF. In the presented study, strict criteria for PFF and TFF was defined. Only clear definitions will engage the collection of comparable data. Retrospective study design without standardization is often of poor data quality due to incomplete follow up data and different investigators. However, data collection over 19 years by a single investigator appears to be impractical. Loss and removal of the whole graft are clear parameters for TFF. From the clinical course and as a result of perfusion disorder through its vascular pedicle, TFF is an early flap failure. Therefore, minor, insufficient perfusion of flap elements leads to malnutrition, and thus to consecutive (sub-)total loss of skin paddle and/or bone segments. This was defined as PFF. PFF therefore does include the functional use of the flap and appears as a late flap failure. Most published data lack a differentiation between soft and hard tissue loss. Partial flap failure was reported with an incidence of 3–14% but has not been further differentiated in most cases (Table 4).
A retrospective single-center study on 129 FFF transfers over the last 20 years found TFF in 12.4% and PFF in 7.8% of cases [21]. An investigation on 20 virtual planned FFF showed that preoperative planning based on preoperative CT-scan allows to include the preoperatively planned skin paddle area [13]. Another clinical trial included preoperatively marked perforator vessels for skin paddle in digital planning and noted a survival rate of 92% (n = 24) in FFF transfer with three total and two partial skin paddle losses [12]. Other investigators observed seven total flap losses and three losses of skin paddle in a total of 99 FFFs [16].
In the present study, there were four losses of fibular bone segments and only two of them occurred after radiation therapy (RT). Loss of the skin paddle occurred in two cases of maxillary reconstruction and in nine cases of uni- and poly-segmental reconstruction of the mandible. After an average time of 27 days (median: 22 days, range 2–67 days), partial loss of the skin paddle was observed whereas partial bone loss occurred after mean 181 days (Median: 101.5 days, range 37–499 days). Swelling and edema are results of ongoing inflammatory processes and wound healing immediately after surgery. A critically reduced perfusion of the septo-cutaneous perforators could be the consequence. Its maximum dimension can be expected 2–3 days after surgery. The unusually late appearance of visible (sub-)total dysfunction of the skin paddle perfusion after more than the median time of 3 weeks should be interpreted with caution and as result of documentation bias. Any influence of RT in this respect can be excluded, since RT always started after PFF was already observed. The onset of adjuvant RT in the group PFF skin was at median 50.5 days (range 39–114 days) after surgery in comparison to the control group comprising complete flap success (n = 40), in which RT began in median 49 days (range 21–98 days) after surgery. A statistically significant difference could not be observed. However, an adjuvant RT for oncologic reasons was not to be delayed by a PFF. The results must be interpreted with caution due to the small number of cases. In the literature, the effect of prior irradiation on partial or complete loss of FFF compared with unirradiated grafts has often been reported to be statistically insignificant [38,39,40,41,42]. The effect of postoperative irradiation on partial flap failure in microvascular head and neck reconstruction has not been well described in literature and indicates that further studies are needed in this area. Verhelst et al. focused on perioperative irradiation but it was not identified as a statistically insignificant risk factor for flap failure [21]. In a study by He et al., 9 of 17 patients were irradiated postoperatively and all grafts sustained [43]. In this study, no cases of PFF were detected during or after RF. Under RT conditions, PFF could be similar to radiogenic oral mucositis, which is associated with an early inflammatory response [44,45]. These factors provide a target for biology-based mucositis-prevention strategies [46,47], and thus for PFF prevention. Further, the option of an additional skin paddle for defect closure after oncologic resection is without doubt one of the major advantages of the FFF in addition to its clinical and technical function of flap monitoring. On the other site, wound healing disorder of the donor site after skin paddle harvesting appears at a rate of 1.07–31.2% [23,48,49]. In literature, different techniques for closure of the donor site have been described [50]. Focused only on monitor function, the price for an unreliable monitor skin paddle seems to be high and should be critically reflected. Nevertheless, some authors believe that the reliability of the skin paddle for the closure of recipient site defects is insufficient in non-irradiated [51] and especially in irradiated patients [52]. In a retrospective investigation, Thome et al. observed 20% of skin paddle failures (n = 27) and came to a similar conclusion [53]. Other authors found a stable and sufficient vascular supply of the septo-cutaneous skin paddle by the septum intermusculare posterius and perforator vessels around the musculus soleus [54,55,56]. They emphasize the necessity of a muscle cuff around the posterior septum, which contains vessels that are crucial for skin paddle survival [24].
Partial bone loss may occur more frequently than previously observed and described in the literature as a result of malnutrition. Sufficient neovascularization to allow free-flap survival independent of the vascular pedicle has been reported to occur within 7 to 10 days in myo-cutaneous flaps [57,58,59]. In contrast, a comparative prospective clinical study measured hemoglobin oxygenation and capillary flow in 50 flaps (25 forearm flaps, 15 osseo-cutaneous fibular flaps, and 10 anterolateral thigh flaps) at 4 and 12 postoperative weeks. The authors found that flap autonomization rates were significantly higher in the lower jaw and non-irradiated defect sites. In addition, fascio-cutaneous flaps were found to be autonomized faster than osseo-myo-cutaneous free flaps. Myo-cutaneous flaps were never found to be autonomized after 4 weeks [60]. Kumar et al. studied blood supply of fascio-septo-cutaneous free flaps several months after surgery and found no significant blood flow through vessels across the flap inset [59]. Mücke et al. found that osseo-myo-cutaneous free flaps are significantly dependent on vascularity of the original anastomoses even 1 year after surgery [60]. According to their data, our findings should be interpreted as an adverse effect of radiation therapy (n = 2) and two “real” partial bone segment failures. The risk to develop osteoradionecrosis is decreased in patients with high body mass indices and on steroid therapy [61] through adequate soft-tissue bulk paired with the high-quality vascularized fibula bone [62]. Data published in the literature show that osteoradionecrosis of the original mandible occurred after a median time of 10.9 months (range 1.8–89.7 months) after RT and 90% occurred within 37.4 months [63]. In contrast, our data show bone loss after a median time of 3.38 months (range 1.23–16.63 months) and more than 6 months earlier. This observation should be interpreted with caution due to the low number of cases and should be further studied in larger study groups.
Early TFF was incident in n = 3 maxillary and n = 17 mandible reconstructions. TFF was found after mandible reconstruction in anterior defects (Classes III-IV, 3 out of 17 cases, 17.6%) and more frequently in lateral defects (Classes I–II, n = 14, 82.4%). Uni- and bi-segmental were commonly used for these Classes I–II reconstructions. Reasons for increased TFF in class I and II were critical pedicle course (inner surface of mandible and mouth floor), kinking of the vascular bundle [64] and length [21,65,66]. In addition to known general risk and complicating factors, further risk factors for flap failure include postoperative swelling and edema, hematoma, movement of the neck, circular tracheal tube fixation loop, and course of the vessel through the neck [33].
The therapeutic procedure for partial skin or isolated bone loss depends on the jaw affected. If PFF of the skin paddle occurs in the maxilla, it is usually an uncritical situation and wound healing from peri-osseous tissue can be expected. When bone loss in the maxilla occurs, a “simple” prosthetic rehabilitation by obturator prosthetic is a therapeutic alternative [67,68] if another microvascular bone graft is not desired. Large defects can be downsized with local tissue advancement. Functional impairment (eg. scars) might be addressed in a two-staged procedure. Safe flaps routinely used in our department are the temporal myo-fascial [69], pectoralis major [70,71], and deltopectoral flaps [72].
In the mandible, skin paddle loss is often noncritical when the primary bone graft is vital. After wound healing local flaps and staged scars, loosing procedures can be necessary to improve dysfunction such as trismus [73]. Flaps of choice in this situation are often radial forearm [74], pectoralis major [70,71], and deltopectoral flaps [72]. When PFF of bone segments or TFF after mandible reconstructions appear, there are different strategies available that need to be evaluated in light of the patient’s condition. If patient’s condition is poor and the avital graft showed no signs of inflammation, it was left in the oral cavity (Figure 6). If inflammation and/or loosening of osteosynthesis material occurred around the avital segment, removal is necessary. Sometimes further use of osteosynthesis is possible, especially if patient-specific osteosynthesis was used. However, in the majority of cases, removal of the osteosynthesis will become necessary (Table 3). Re-osteosyntheses could be useful in combination with distant flaps like pectoralis major flaps, deltopectoral flaps, and bone hip grafts. The staged procedure of second attempts microvascular bone graft is possible after critical evaluation. The removal of the avital graft and the anticipation of stable scars building and “functional” pseudarthrosis is a further option (Figure 6).
4.2. Influence of Age at Flap Transfer, BMI, ASA-Score and Risk Factors in Terms of Flap Success in Relation to PFF and TFF
In this study, no significant differences between patients’ age at flap transfer and flap outcome were observed. This confirms other investigations that patients’ age at flap transfer is not crucial for flap success [75,76]. It is a surrogate parameter for the general condition of the patient [77,78]. A prospective study on 215 patients found that age ≥ 70 years had a significantly higher ASA-Score and shorter duration of surgery. Age was a risk factor for longer ICU stay and complication rate. They found no influence of age on the length of hospital stay and overall success of microvascular reconstructions [79]. In this study, more than 92% were rated ASA 2 or 3. All partial flap failures and all but one total flap occurred in both groups. ASA score and duration of the operation were found to be independent risk factors for operative revisions [76]. In literature, ASA-Rating is correlated with a higher number of postoperative complications after microvascular reconstructions [80,81] and the overall survival [82]. We calculated the relation between ‘Age at flap transfer’ and BMI and found an evenly distributed pattern.
Concerning alcohol and tobacco abuse in the investigated group, no statistically significant differences were found. In published literature, alcohol abuse was identified as a risk factor for postoperative adverse events [82]. Tobacco abuse was shown to reduce overall survival time compared with non- and never-smokers [83,84]. A review by Van Imhoff et al. stated that survival rates are lower and recurrence rates are higher in patients who continued to smoke after having being diagnosed with Head and Neck SCC in comparison to patients who stopped smoking [85].
BMI had no statistically significant influence on flap success in this study. Low BMI or underweight at diagnosis was an independent, unfavorable prognostic factor [86,87]. Obesity was associated with better outcome and was not an independent risk factor for postoperative complications of free tissue transfer [88,89]. Other investigators found that higher BMI/obesity is a risk factor for peri- and postoperative medical complications [90].
The duration of hospitalization was calculated with a mean of 22.6 days in the PFF group and a mean of 33.8 days in the TFF group. Statistically significant differences (p = 0.038) were found in the occurrence of partial or total flap failures (Table 1). While the majority (68.75%, n= 11 out of 16) of all partial flap failures are a dysfunction of the skin paddle failures (mean duration of hospitalization partial flap loss group 20.71 days), we conclude that loss of that skin loss does not result in significantly longer hospital stay than in total flap losses. Stepwise removing of avital flap parts, deperiostizing of the bone graft, and covering with oral mucosa is an attempt for flap salvage. However, the initial stay at the ICU seems to have no statistical influence concerning upcoming PFF or TFF. It was calculated in both groups with a mean of approximately 2.0 days.
No statistically significant difference concerning mean operating time (PFF: meantime 546 min, TFF: meantime 524 min) and flap outcome was found. Surgery time is described as a risk factor for postoperative complications [91,92,93]. Increased operating time may also be the result of a younger surgeon learning and being taught by an older instructing surgeon. However, operating time should be reduced whenever possible [92]. The study could not include ischemia time in the risk analysis because this parameter was not recorded or was incomplete.
4.3. PFF and TFF in Non-VSP vs. VSP and Reconstruction Methods (Immediate vs. Delayed)
The majority of isolated skin paddle losses occurred in the non-VSP group. Reasons can be seen in mechanical trauma and manipulation during free-hand transplant forming i.e., preparation of bone segments and revised application of osteosynthesis. Individually custom-made cutting guides stabilize and preserve intersegmental connectors for stabilization of several bone segments, which provide a valuable support on the vascular pedicle during transplant preparation and shaping.
No statistically significant differences were found concerning patients’ preoperative planning procedure (non-VSP vs. VSP) and time of reconstruction (immediately vs. delayed). The results confirmed the findings of other clinical investigations [94]. A retrospective study of 128 osseous free flaps with a minimum follow-up of 12 months evaluated plate-related complications in patient-specific versus conventional fixation systems. They found more complications with patient-specific plates (e.g., wound healing disorders, plate exposure, fixation failure, and subtotal osseous union) in comparison to conventional reconstruction plates, but the differences were statistically insignificant.
One possible reason for (sub-)total bone loss despite maintained perfusion of the vascular pedicle might be trauma during preparation, segmentation, and shaping of the fibula graft. Preoperatively planned and fabricated saw guides and patient-specific implants ease and accelerate the surgical procedure itself, which should be helpful in avoiding mistakes and facilitating the handling of the fibula graft. More complex shaping and osteotomization of bone segments leads to manipulation of the vascular pedicle during dissection and puts it at risk [22]. Furthermore, the impact of VSP and patient-specific plates in terms of wound healing abnormalities, plate exposure, and subtotal osseous union shows a trend towards increased complication rates compared with non-VSP with hand-bended plates. Plate-related complications were increased with radiotherapy and multi-segment flaps [95].
Further investigations on partial flap loss of osseomyocutaneous FFF are needed.
5. Conclusions
The fibula free flap constitutes a standard therapy for jaw reconstructive surgery. The present results of 180 fibula free flap over a period of 19 years shows a cumulative success rate of 88.9%, which is well comparable with other studies. The findings of our long term monocenter retrospective investigation are a position statement about flap success and partial and total loss rates, which was achieved by careful patient selection and a two team approach to reduce operating time. In partial or total flap failure, no statistically significant correlation was observed between patient age, sex, ASA, BMI, alcohol and tobacco abuse, time, and method of reconstruction (virtual versus non-virtual surgical planning). Total flap failure caused significantly prolonged hospitalization time. Partial flap failure affected mainly the skin paddle. Two-thirds of these cases were found in the non-VSP group and only two cases were observed in the virtual surgical planning group. This could be attributed to protective effects of the cutting-guide template, which possibly decrease the mechanical trauma during surgery.
Acknowledgments
The authors are grateful for the consent of the patient for presented X-rays and clinical images. This publication is part of the second author’s dental doctoral thesis (SS).
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Author Contributions
Conceptualization, M.K.; methodology, S.S., M.K., C.B.; formal analysis, M.K.; investigation, M.K., and S.S; data curation, M.K. and S.S.; writing—original draft preparation, M.K., S.S., S.A. and S.B.; writing—review and editing, M.K., S.S., S.A., C.B., D.S., H.-P.H. and S.B.; visualization, M.K., D.S., H.-P.H. and S.A.; supervision, M.K., H.-P.H., S.B. and S.A.; project administration, M.K. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Justus-Liebig University Giessen (AZ35/20, approval 25.5.2020).
Informed Consent Statement
Patient consent was waived as the study is a retrospective data analysis.
Data Availability Statement
The data presented in this study are available upon request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Schematic illustration of reconstructive workflow and stratification in partial and total flap failure groups. The major characteristic of PFF is the remaining blood supply by the vascular pedicle. In contrast to this, TFF is characterized by interrupted graft perfusion.
Figure 2 Example of ‘PFF skin’ after maxilla reconstruction.
Figure 3 The clinical course of PFF. (OPT 1) Due to the recurrence of an ossifying fibroma (odontogenic tumor) in the ramus ascendens mandibulae in a 22-year-old patient, (OPT 2) a continuity resection and simultaneous reconstruction with a bi-segmental fibula and CAD/CAM plate was planned. (OPT 3) The clinical submandibular fistula had a connection to the plate (Figure 4A). (OPT 4) An OPT image was obtained after removal of the avital fibular segments and re-stabilization of the remaining graft. There is initial evidence of incipient bone healing on the proximal resection-site. (OPT 5) Follow-up visit at 9 weeks after re-stabilization. In the condylar segment, bone healing is pictured, and at the distal segment, progressive resorption is visible. (OPT 6) Progressive bone healing and callus formation originating from the resection site is visible 19 weeks after re-stabilization.
Figure 4 (A) Clinical aspect 4 weeks after reconstruction. After reopening the submandibular approach and excision of the skin fistula, there was no evidence of screw loosening. Temporary unscrewing of the screw (No. 5) leads to bleeding. (B) With a new fistula, the site was reentered 8 weeks after surgery and the screw was removed again. There was no clear bleeding from the screw hole. In addition, the anterior-caudal edge of the bone was removed.
Figure 5 (C1) The CAD/CAM plate was removed 14 weeks after surgery when the fistula was productive again. (C1–C3) A sharp demarcation line caudal to the crestal edge of the plate became visible and was conspicuous. (C2) Between the fibula segments, an incipient ossification of the gap was observed. The underlying bone was pale. (C3) The bone was removed caudally. The bone marrow was replaced by granulation tissue and was removed. (C4) The intersegmental ossification was not yet sufficient so that stabilization again was necessary.
Figure 6 The following OPTs outline the clinical course of TFF in a 76-year-old patient in good general condition who suffered from osseous metastasis of prostate cancer and underwent FFF. (OPT 1) A pathologic fracture occurred after the removal of necrotic bone in the right lower jaw in the setting of bisphosphonate induced MRONJ stage III (treatment with Zoledronacid/Denosumab in prostate cancer) [28]. (OPT 2) Virtual planning of double-barrel fibula was performed. CAD/CAM plate was used for stabilization and the simultaneous insertion of two dental implants was performed. (OPT 3) At 3 weeks post-surgery, the skin paddle was lost. A surgical exploration ended with the removal of an avital distal graft segment and modification of the plate in situ. The vascular pedicle of the remaining FFF still rendered a clear signal in the Doppler ultrasonic probe. (OPT 4) At 16 weeks after surgery, the remaining graft segment also had to be removed in the setting of continued inflammation and the absence of a Doppler signal. (OPT 5) At 22 weeks after surgery: The screws loosened in the anterior mandible segment so that the remaining plate with teeth 32–42 and a bone sequester had to be taken out.
Figure 7 Partial or total flap failure in relation to the number of fibula segments (p = 0.114).
Figure 8 Kaplan–Meier function was drawn for the three sub-groups of PFF. The abscissa axis “time” (days) is drawn on a logarithmic scale.
Figure 9 Comparison of the onset of adjuvant radiation therapy between the groups of complete flap success (n = 40) and PFF skin (n = 4).
Figure 10 TFF concerning the first clinical signs of flap necrosis and time of removal of the avital graft was visualized by Kaplan–Meier function. The abscissa axis “time” (days) is drawn on a logarithmic scale.
Figure 11 TFF analysis. Clinically diagnosed flap necrosis and further surgical interventions (removal of graft) are shown according to jaw location (maxilla or mandible) in the postoperative time course. The ordinate axis “time” (days) is drawn on a logarithmic scale.
cancers-13-00865-t001_Table 1Table 1 Clinical details of partial (PFF; n = 16) and total flap failures (TFF; n = 20) after jaw reconstruction with fibular free flaps.
N = 36 PFF
N = 16 (44.4%) TFF
N = 20 (56.6%) p-Value
Age (years), SD 59.9 ± 14.4 62.5 ± 9.5 p = 0.520
Follow-up (months), SD 48 ± 42.9 31.5 ± 31.6 p = 0.193
Type of flap loss
PFF, Skin paddle 11
PFF, Bone segment 4
PFF, Both 1
Total flap loss (TFF)
20
Sex
Female 5 6 p = 0.609
Male 11 14
Diagnosis
Benign tumor
Malignant tumor
MRONJ
ORN 1
15
15
2
3
Reconstruction
Immediate 14 17 p = 0.610
Delayed 2 3
Reconstruction
Non-VSP 10 10 p = 0.341
VSP 6 10
Neck dissection
Unilateral 11 13 n.s.
Bilateral 3 3
None 2 4
Tracheostomy
None 6 8 n.s.
Primary 9 11
Secondary 1 1
Irradiation
Preoperative 1 3 n.s.
Postoperative 8 4
None 7 13
Risk factors
Alcohol abuse 5 9 p = 0.348
Tobacco abuse 9 13 p = 0.546
Operating time (min) 546.2 ± 94.9 524.4 ± 97.2 p = 0.504
Duration ICU (days) 2 ± 1.3 2.1 ± 1.7 p = 0.847
Hospitalization (days) 22.6 ± 9.7 33.8 ± 18.8 p = 0.038
BMI
≤18
18 ≤ 25
25 ≤ 30
30 ≤ 35
>35
9
3
4
1
9
7
2
1
ASA-Score
ASA 2 10 7
ASA 3 6 12
ASA 4
1
n.s. = not significant; ORN, Osteoradionecrosis; MRONJ, Medication-related osteonecrosis of the jaw; VSP, virtual surgical planning; BMI, Body mass index; SD, standard deviation.
cancers-13-00865-t002_Table 2Table 2 Table depicting the locations according to the classification by Brown et al. where PFF (n=16) and TFF (n=20) occurred [29,30].
Type of Defect PFF Skin (n = 11) PFF Bone (n = 4) PFF Both (n = 1) TFF (n = 20)
Maxilla
II 1 - - 2
III 1 - - 1
Mandible
I
4
-
1
7
Ic - - -
1
II
2
2
-
6
IIc - 1 - -
III
3
1
- 2
IV - - -
1
cancers-13-00865-t003_Table 3Table 3 Clinical details of total flap failures (n = 20).
N = 20 Maxilla (n = 3) Mandible (n = 17) Overall (n = 20)
p
Age (years), SD 73.3 ± 1.8 60.6 ± 8.9 62.5 ± 9.5 p = 0.001 ^
Follow-up (months), SD 10.3 ± 9.7 35.2 ± 32.8 31 ± 31.6
The earliest sign of flap dysfunction (days) 3. 3 ± 3.5
(Median 3) 14.4 ± 11.1
(Median 10) 12 ± 10.9
(Median 8.5) p = 0.007 ^
Surgical validation and avital flap treatment procedure (days) 54 ± 60.1
(Median 36) 92.1 ± 132.0
(Median 21) 86.5 ± 123.6
(Median 22.5) p = 0.449 ^
Anastomosis revisions 2 6 8
Arterial thrombosis ‡ 2 2 4
Venous thrombosis ‡ - 4 4 n.s
Unknown 1 11 12
Explantation of bone graft 2 16 18
Osteosynthesis (PSI) removal 1 11 12
Re-osteosynthesis - 3 3
Second flap 1 8 9
Temporalis muscle flap 1 1 2
Deltopectoral flap - 1 1
Pectoralis major flap - 2 2
RFF - 1 1
FFF - 2 2
Hip graft (non-DCIA) - 1 1
‡ Kind of thrombosis was evaluated during microsurgical revision. (n.s. = not significant; ^ Equal variances not assumed; DCIA, deep circumflexia iliac artery; PSI, patient-specific implant; SD, standard deviation; RFF, radial forearm flap).
cancers-13-00865-t004_Table 4Table 4 Overview of FFF total and partial flap failure rates in the literature.
Authors Investigation Period
n
Total Flap Failure Partial Flap Failure
This study 2002–2020 180 11.1% 8.9%
Colletti et al. [16] 2002–2010 99 7% 3%
Gallegos-Hernandez et al. [35] 1996–2006 87 16.1% -
Götze et al. [12] 2013–2015 24 12.5% 8.3%
Lopez-Arcas et al. [36] 1992–2006 117 - 8.5%
Momoh et al. [23] 2005–2009 157 1% 14%
Mücke et al. [37] 2009–2013 76 9.2% -
Seruya et al. [22] 2003–2012 68 4.41% 11.76%
Shroff et al. [14] 2009–2013 30 6.66% -
Verhelst et al. [21] 1996–2016 129 12.4% 7.8% | Recovering | ReactionOutcome | CC BY | 33670721 | 19,661,708 | 2021-02-18 |
What was the administration route of drug 'ALENDRONATE SODIUM'? | Conservative Management of Medication-Related Osteonecrosis of the Jaws (MRONJ): A Retrospective Cohort Study.
BACKGROUND
Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of bisphosphonates and anti-resorptive drugs prescribed for treatment of severe osteoporosis, Paget's disease, and bone malignancies. The aim of this study was to evaluate the clinical outcome of a combined pharmacological and surgical management strategy on patients affected by MRONJ.
METHODS
Medical records of patients with MRONJ were retrospectively examined to collect clinical history data. Conservative management included an initial pharmacological phase with antibiotics and antiseptic agents, followed by surgical intervention to remove bone sequestrum. Primary outcomes were healing from MRONJ at short term (1 month after surgery) and at longer term (3 months after surgery). Secondary outcome was assessment of recurrences at longer-term follow-up.
RESULTS
Thirty-five patients were included in the study with mean follow-up of 23.86 ± 18.14 months. Seven cases showed spontaneous exfoliation of necrotic bone during pharmacological therapy, which in one case did not require any further intervention. At 1-month posttreatment, 31 out of 35 (88.5%) patients showed complete healing. The 25 patients who were followed for at least 3 months revealed a healing rate of 92% (23/25). Recurrences occurred in 7 patients out 23 who showed the long-term healing, after a mean period of 7.29 ± 3.45 months. The prognostic score (University of Connecticut Osteonecrosis Numerical Scale-UCONNS) was significantly higher (p = 0.01) in patients with poor healing as compared to complete healing, both at 1 and 3 months posttreatment.
CONCLUSIONS
A MRONJ treatment approach based on a combined pharmacological and surgical treatment strategy showed a high rate of healing and few recurrences.
1. Introduction
As defined in 2014 by the American Association of Oral and Maxillofacial Surgeons (AAOMS), medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of bisphosphonates and of certain anti-resorptive drugs, such as denosumab [1], commonly prescribed for controlling severe osteoporosis, Paget’s disease, and bone malignancies, including multiple myeloma and bone metastases [1]. Bisphosphonates (BPs) are analogues of inorganic pyrophosphate, inhibiting the pyrophosphate-dependent enzymes mediating bone resorption [2]. Denosumab is a human monoclonal immunoglobulin G2 subclass (IgG2) that mimics the function of the endogenous molecule osteoprotegerin (OPG), reducing bone metabolism [3]. Even if the potential of BPs and denosumab to increase the survival in cancer patients remains uncertain, they significantly improve the quality of life, reducing bone pain in cases of advanced bone metastases [4].
MRONJ pathogenesis is still largely unknown. A multi-factorial mechanism has been advocated, involving inhibition of angiogenesis and remodeling in bone tissue, presence of continuous micro-trauma within the oral cavity during eating and speaking, as well as a potential role and impact from oral mucosal inflammation or odontogenic infection [5,6].
A recognized risk factor for MRONJ is high concentration and long duration of BP intake [7]. The frequency of MRONJ in cancer patients has been estimated, ranging from 1% to 15%, while the frequency in patients with osteoporosis, receiving much lower BP doses, is estimated around 0.001% to 0.01% [8,9]. Antiangiogenic agents, tyrosine kinase inhibitors, and monoclonal antibody-targeting Vascular-Endothelial Growth Factor (VEGF)—such as sunitimib, sorafefenib, bevacizumab—worsen the risk of MRONJ from 5- to 10-fold [1,10]. Since MRONJ negatively impacts patient quality of life [11], preventive dental treatment is strongly recommended [12].
Despite no international consensus for treating MRONJ, a decisional tree to manage these patients requires consideration of the staging of MRONJ, patient age, gender, and systemic health [9]. The primary objective of treatment is to control symptoms, mainly pain, and to avoid progression of MRONJ to a more advanced stage [13]. Recent studies suggest a need for early surgical management to ensure complete removal of the necrotic bone following implementation of a first-line conservative nonsurgical approach with antibiotics, antimicrobials, and analgesics [13,14,15,16,17]. Surgery, in particular, is recommended in the presence of well-defined bone sequestra; in these cases, sequestrectomy or surgical debridement is needed. In patients with advanced stages who show a progression of the disease, or in cases of persistent pain and infection despite the medical therapy, an extensive resection is required [1,18,19]. Medical therapy itself appears to control pain and infection in about 50% of patients. A risk of sepsis, mainly in immunocompromised cancer patients, further justifies surgical intervention [19]. To date, MRONJ surgical therapy has been associated with variable percentages of success due to high heterogeneity among published studies [18,20,21].
The aim of this study was to retrospectively assess the success and recurrence rates in a cohort of MRONJ patients treated with a first pharmacological phase, intended for isolating gradually necrotic bone tissue and promoting sequestration, followed by a surgical intervention limiting the need for extensive resections.
2. Materials and Methods
2.1. Patients
2.1.1. Study Design and Patient Population
This cohort study retrospectively analyzed clinical records of MRONJ patients referred to the Oral Medicine Unit (ASST Santi Paolo e Carlo) at University of Milan, from October 2008 to December 2017. MRONJ staging of affected patients was defined according to 2014 AAOMS criteria [1].
2.1.2. Eligibility Criteria
The inclusion criteria included patients with MRONJ diagnosis at stage I–III, according to AAOMS criteria [1,21]. All patients were treated first with a pharmacological phase and then a surgical phase for bone sequestration removal [1,13,14,15,16,17]. The exclusion criteria were [1]: history of radiation therapy to the jaws or obvious metastatic disease to the jaws, no history of pharmacological therapy for MRONJ, and no history of surgical removal or spontaneous exfoliation of bone sequestra.
2.1.3. Treatment Intervention
Each patient received two phases of management, i.e., a pharmacological phase and a surgical phase. Based on previous literature [1,13,14,15,16,17], the protocol first used a medical management approach with antibiotics and local measures and followed the patients until there was evidence of bone sequester formation. At that point, surgical treatment of the MRONJ lesion site was performed with the goal of removing the sequestered bone and debridement of the site. In recurrent cases, the patients were referred to maxillofacial surgeons for major surgical procedures, i.e., bone resection.
Based on previous studies [1,9,21,22], systemic antibiotics were prescribed to all study patients as follows: amoxicillin 3 g/day or clindamycin 1800 mg/day in cases of allergy to the penicillin; for the cases scarcely responsive to single-antibiotic therapy, metronidazole 500 mg/day for a maximum 14 days. Topical antiseptic therapy with 0.2% chlorhexidine mouthwash and 1% chlorhexidine gel, applied onto exposed necrotic bone, was also prescribed [17].
Surgical intervention (sequestrectomy) was performed when sequestered bone was clinically or radiographically evident and not spontaneously exfoliated, following a MRONJ protocol previously recommended [23]. Briefly, one week before surgical intervention, each patient received the dental scaling, topical antiseptic therapy (0.2% chlorhexidine mouthwash, twice/day), and the prescription of antibiotic therapy started three days before the surgery (amoxicillin 3 g/day, or clindamycin 1800 mg/day in case of allergy to penicillin) [23]. On the day of surgical intervention, under local anesthesia, necrotic bone was removed via full-thickness mucoperiosteal flap, with minimal trauma to the cortical plates. Teeth involved in the necrotic area were extracted and a meticulous bone curettage and osteoplasty were performed until clear bleeding and white vital bone were clinically evident. The flap was closed with an absorbable suture via periosteal releasing incisions to achieve primary closure and in order to maximize the vascular supply to the area as well as to reduce risk of infection at the surgical site. Post-surgery, patients continued for two weeks the systemic antibiotic therapy and antiseptic mouthwash and also applied 1% chlorhexidine gel onto the surgical wound twice/day for at least 14 days. On the basis of the promising results obtained in previous studies [24,25,26], and under approval of the patient’s oncologist, pentoxifylline and tocopherol were also prescribed per os (pentoxifylline 800 mg/day + tocopherol 800 U.I./day), before and/or after surgical intervention, according to clinical case.
2.2. Data Collection
Clinical and demographic data collected for each patient included, age, gender, systemic conditions, MRONJ stage [1], bisphosphonate, anti-resorptive, or anti-angiogenetic therapy (dosage, suspension, and duration), formation of bone sequestra, area of exposed bone (localization and size), date of surgical intervention(s), number of recurrences, and length of follow-up. The duration of therapy was determined as the period from the start of treatment to the first visit to our clinical unit. The prognostic score (University of Connecticut Osteonecrosis Numerical Scale—UCONNS) described by Landesberg was applied to find possible correlation between outcomes and patient systemic conditions [27]. UCONNS scores assess the individual prognosis based on known risk factors for MRONJ management failure, including systemic health conditions, comorbidities, type, and duration of bisphosphonate therapy and type of intervention performed. UCONNS scores were categorized as follow: 0–8, 9–16, 17–24, 25–32.
2.3. Outcomes
2.3.1. Primary Outcomes: Clinical Healing
The following criteria for clinical healing were used (adapted from [28]):Short-term healing—A patient was defined as “healed at short-term”, if presenting, for at least 1 month after sequestrectomy or spontaneous exfoliation of necrotic bone, the following clinical picture: absence of exposed necrotic bone or bone that can be probed through a fistula; absence of purulent drainage; absence of edema and stimulated pain; complete mucosal coverage of the surgical site.
Long-term healing—A patient was defined as “healed at long-term”, if presenting the same clinical picture described above but lasting for at least 3 months after sequestrectomy or spontaneous exfoliation of bone sequestration.
Stable MRONJ clinical picture—A patient was “stable” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with the same stage seen during the first visit.
Worsened MRONJ clinical picture—A patient was “worsened” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with a worse stage than found at first diagnosis.
Improved MRONJ clinical picture—A patient was “improved” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with a better stage than the one of the first diagnosis.
2.3.2. Secondary Outcomes: Rate of MRONJ Recurrence
Recurrence
Recurrence was defined as the appearance of exposed necrotic bone or bone that could be probed through a fistula, in association or not with radiographic evidence of architectural bone changes persisting for more than 8 weeks in an area that had already demonstrated a long-term healing.
Adverse Effects
Any adverse events due to pharmacological and/or surgical phases were recorded when specified in the medical record.
2.4. Statistical Analysis
Means and standard deviations were calculated for continuous variables; Kolmogorov–Smirnov test of normality was applied, and data were normally distributed. A t-test was used to compare means between two unpaired samples. For categorical variables, extracted data were expressed as percentages, and statistical analyses to identify significant differences were performed by applying the χ2 test using the online Graphpad statistical software (GraphPad Software®, San Diego, CA, USA). Statistical significance was set at p ≤ 0.05. Odds ratios were also calculated using the online MedCalc Software Ltd statistical software (MedCalc Software Ltd., Ostend, Belgium).
2.5. Ethical Approval
The study was performed under ethical approval obtained from the Ethic Committee of the AO San Paolo (ID study approval: ONM-BF-Gene, 2016). Opt-out patient consent was obtained.
2.6. STROBE Statement
The Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement was used to prepare this report.
3. Results
From an initial cohort of 45 patients with MRONJ, 35 subjects were included in the study. Ten patients were excluded for the following reasons: positive anamnesis for head and neck radiotherapy (n = 2), or insufficient clinical data (n = 8). Figure 1 provides a flow-chart of enrolled study patients, while patient demographic and clinical data are summarized in Table 1.
Most of patients were women (χ2; p = 0.02); the mean age of study participants at the first examination was 73.46 ± 9.29 years (range 51–93 years) (Table 1). Six patients out thirty-five were undergoing anticancer chemotherapy at the moment of surgical intervention. Eight patients were receiving intravenous steroid treatment, which in four cases was associated with the chemotherapeutic regimen (Table 1). Six patients were also affected by diabetes.
Most patients were treated with zoledronate and showed stage II MRONJ lesions (Table 1).
The mean follow-up of patients, from the first visit up to the last one available, was 23.86 ± 18.14 months (range: 1–74 months). The mean therapy with zoledronate lasted 34.29 ± 33.42 months; in some cases, the drug was suspended for a mean period of 8.53 ± 20.21 months. The mean duration of alendronate therapy was longer (79.42 ± 63.33 months), with a mean suspension period, when occurring, of 13.15 ± 19.58 months. The mean duration of the therapy with denosumab was shorter, lasting 15 ± 7.94 months, with a mean suspension time of 0.8 ± 1.1 months (Table 2).
The pharmacological phase involved the use of topical chlorhexidine and systemic amoxicillin, with 11 patients also receiving metronidazole. In nine patients (25.71%), the supportive pharmacological therapy for MRONJ included also pentoxifylline and tocopherol (mean period of administration 3.81 ± 2.46 months).
Seven cases showed spontaneous exfoliation of necrotic bone. In four cases, the exfoliation occurred during the pharmacological phase: in one case, the sequestrum was completely exfoliated not requiring any further intervention, while in three patients the sequestra were partially exfoliated, requiring the further surgical intervention at the same site. In the other three patients, a spontaneous exfoliation of an additional bone sequestrum followed sequestrectomy.
Fifty-seven interventions of sequestrectomy were performed. Eighteen patients received a single surgical intervention, while four patients underwent two interventions in two different sites affected by MRONJ. In five subjects, the interventions were more than two; one patient required five interventions at the same site.
Figure 2 describes a clinical case where antibiotic administration gradually resulted in the isolation of bone sequestrum from the surrounding healthy bone.
Figure 3A–F describes the surgical intervention for bone sequestrum removal in a patient who developed MRONJ after zolendronate intake for oncological reasons (metastases of breast carcinoma).
3.1. Primary Outcomes
3.1.1. Short-Term Healing
At 1-month post-surgery, 31 out 35 (88.57%) patients showed complete healing. The four not-healed cases were MRONJ stage II: in two cases the picture was stable at last follow-up, while the other two demonstrated a worsening of their conditions. These four patients received zolendronate (in one case alternating to denosumab) for oncological reasons for a mean period of 18.66 ± 4.72 months (range 17–60 months). Two of them had suspended the drug for 10 and 13 months. The mean UCONNS prognostic score was 15.83 ± 7.24 in healed patients, 25 ± 4.08 in not-healed patients (t-test, p = 0.01). Figure 4 describes the short-term healing outcomes depending on UCONNS score.
3.1.2. Long-Term Healing
Twenty-five patients had long-term follow-up (at least 3 months), while the other ten patients, including two patients who did not heal at short-term, were lost prior to further follow-up. In the 25 patients, the mean follow-up was 27.28 ± 15.37 months from the first visit. Twenty-three out 25 (92%) showed complete healing of the surgical site for at least 3 months after surgery (Figure 5). Two patients were not healed at either short-term or long-term follow-up. One of them showed a stable MRONJ lesion in the posterior maxilla, while the other patient with MRONJ at the mandible showed a worsening clinical picture. This patient was referred to maxillofacial surgeons for major surgery. Both not-healed patients had MRONJ stage II and received zoledronate for oncological reasons, respectively for 24 and 17 months. One of the patients was under current zoledronate treatment (in addition to chemotherapy), while the other patient had suspended the drug 13 months before. The mean UCONNS prognostic score was 16.56 ± 7.63 in healed patients, as compared to 22.5 ± 0.7 in not-healed patients (t-test, p = 0.001).
Table 3 reports healing outcomes at long term in patients who received also pentoxifylline and tocopherol therapy.
3.2. Secondary Outcomes
3.2.1. Recurrences
Recurrences were recorded in seven patients out 23 (30.4%) who showed long-term healing: two were stage I, four at stage II, and one was at stage III. The recurrences occurred on average 7.29 ± 3.45 months after surgical intervention. Five out of seven patients who showed recurrences were receiving zoledronate for a mean period of 37.2 ± 24.47 months, while the remaining two patients were under therapy with alendronate for a mean period of 84 ± 16.97 months (Odds Ratio—OR:1.81; 95% CI: 0.27 to 11.86; p = 0.53). Recurrence in the oncological group occurred in five out 15 healed patients, while considering the osteoporotic group in 2 out 8 healed patients (OR 1. 50; 95% CI: 0.21 to 10.30; p = 0.68) (Figure 6).
3.2.2. Adverse Events
No adverse events were reported, except for one case of spontaneous bleeding from the exposed necrotic bone, which occurred soon after the start of pentoxifylline and tocopherol therapy.
4. Discussion
MRONJ is a debilitating condition that more frequently affects females, the elderly, and persons treated for oncological reasons [18,20,28]. Although this complication has important clinical implications for dental practitioners—who need to know the correct management of a patient under anti-resorptive therapy—recent studies highlighted a lack of knowledge among dentists and dental students [29,30,31].
These findings support that, following a combined pharmacological and surgical conservative approach, most patients experience a complete healing. The UCONNS prognostic score was significantly higher in patients with poor healing as compared to those with complete healing in lesions. This conservative approach of MRONJ management was based on previous study outcomes [1,9,21,22] and included systemic antibiotics as well as antiseptic therapy with 0.2% chlorhexidine mouthwash and 1% chlorhexidine gel applied onto exposed necrotic bone [17].
Treatment of MRONJ patients remains challenging, and therapeutic options vary from pharmacological supportive approach with antibiotics and antiseptics to extensive surgical resection of necrotic bone. According to previous studies [14,18,20,32,33], an early surgical approach with appropriate resection margins and primary wound closure can ensure a better surgical outcome (mucosal healing without signs of infection) stage improvement at 6 months, with mucosal and radiographic healing evident at one-year posttreatment. Since pharmacological therapy alone rarely leads to lesion healing even at stage I [16], Khan and colleagues [9], in their systematic review, recommended surgical resection with tension-free primary closure.
In our experience, pharmacological management of MRONJ lesions seems to promote progressive isolation of the bone sequestrum, enabling minimally invasive surgical intervention, with a potentially higher rate of long-term success than major surgical resection. Progressive isolation of necrotic bone throughout the preliminary pharmacologic phase allows removal of necrotic tissue without undue sacrifice of healthy bone.
Consistent with previous research findings on conservative management of MRONJ [16,17,21], a high healing rate was achieved in the present study, although the study sample size was small. Importantly, UCONNS scores were confirmed to play a significant role in influencing treatment outcomes. Indeed, similar to a proposed cut-off value of UCONNS scores ≥ 15 to identify a higher rate of therapeutic failure [34], we found that all non-healed (both stable and worse) patients had a UCONNS score beyond 17.
The rate of recurrence after 3-month healing (30.4%), in the present study, appeared similar to that reported by Mucke and colleagues (28.7%), although they performed only surgical debridement in most of their patients [32]. However, due to methodological heterogeneity, a direct comparison among studies remains still complicated, considering that recurrence may occur after several months and that a too short follow-up period may bias the findings.
The additional use of pentoxifylline and tocopherol in treatment of MRONJ lesions is worth further investigation. In this study, most patients healed without major adverse side effects. Only one patient experienced bleeding at the start of pentoxifylline and tocopherol therapy. The Italian drug agency (AIFA) [35] warned of excessive bleeding among patients receiving anticoagulants, thrombolytic agents, and inhibitors of platelet aggregation who simultaneously are administered pentoxifylline and tocopherol. In our study the patient who developed spontaneous bleeding was not under treatment with any of these drugs.
The main limitation of this retrospective study is the use of medical records not specifically designed for the aim of the study. Thus, collected data might be limited in scope, making identification of potential confounding factors difficult, and making patient inclusion into the study prone to selection bias. Further limitations include varying lengths of follow-up of patients and varying patient compliance with the pharmacological protocol, along with the lack of calibration among the oral surgeons who performed the interventions and a lack of standardization in data collection. The retrospective design also predisposes the study to numerous threats to external validity, which limits interpretation and generalizability of the results (such as single-group threat, i.e., the lack of a comparison and/or control groups, and historical threat, where other events, different from the intervention under investigation, can affect the outcomes) [36].
5. Conclusions
An initial pharmacological phase based on antibiotic and antiseptic agents is useful to gradually isolate bone sequestration in MRONJ patients and facilitate a subsequent surgical phase. This approach is particularly advisable for treatment of stages I and II of MRONJ. UCONNS-related prognostic factors play a relevant role in determining the success of MRONJ therapy.
Author Contributions
Conceptualization, G.L. and E.M.V.; methodology, E.M.V., G.L. and N.L.; validation, G.L. and A.S.; formal analysis, G.L. and E.M.V.; investigation, N.L., A.P. and G.V.; data curation, N.L., G.V. and A.P.; writing—original draft preparation, G.V. and E.M.V.; writing—review and editing, N.L. and G.L.; supervision, G.L. and A.S. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of AO San Paolo (ID protocol approval: ONM-BF-Gene, 2016).
Informed Consent Statement
This study is retrospective study. Opt-out patient consent was obtained.
Data Availability Statement
The data presented in this study are available on request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Flow diagram of enrolled patients.
Figure 2 Clinical case of MRONJ localized in left mandible. (A) Cone beam computed tomography (CBCT) images, sagittal and frontal views, showing isolation of mandibular bone sequestration following antibiotic and topical antiseptic therapy (red arrows indicate the bone sequestrum). (B) Necrotic bone sequestration, resulting from the surgical intervention.
Figure 3 Clinical case of MRONJ localized in the upper maxilla. (A) Cone beam computed tomography (CBCT) images, frontal and sagittal views, showing maxillary bone sequestration (red arrows indicate the bone sequestrum). (B) Intraoral clinical view showing the presence of fistula, which demonstrates the presence of infection. (C) Necrotic bone sequestrum removal, after the opening of the surgical flap (mid-crestal incision on the alveolar crest of the edentulous area). (D) The necrotic bone was completely removed until reaching the healthy bone tissue; bone curettage and osteoplasty were performed until vital bone was clinically observed. (E) Primary closure via periosteal releasing incisions using absorbable suture. (F) Follow-up after 3 months from the surgical intervention showing a complete tissue healing.
Figure 4 Comparison of the short-term healing outcomes depending on University of Connecticut Osteonecrosis Numerical Scale (UCONNS) score.
Figure 5 Comparison of the long-term healing outcomes depending on UCONNS score.
Figure 6 Comparison of long-term healing and recurrence in oncological and osteoporotic group.
antibiotics-10-00195-t001_Table 1 Table 1 Demographic and clinical data concerning patient gender, age, comorbidities, concomitant cancer therapies, stage, and localization of medication-related osteonecrosis of the jaw (MRONJ) (n = 35).
Demographic and Clinical Data Number of Patients (%)
Gender
-Male 11 (31.4%)
-Female 24 (68.6%) *
Age, years Years
Range 51–93
Mean, SD 73.46 ± 9.29
Concomitant cancer therapies
-Steroids 4 (11.4%)
-Chemotherapy 6 (17.1%)
-Steroids and Chemotherapy 4 (11.4%)
-No steroids, No Chemotherapy 21 (60%)
Primary disease requiring anti-resorptive drugs
-Breast cancer 10 (28.6%)
-Prostate cancer 4 (11.4%)
-Multiple myeloma 7 (20%)
-Osteoporosis 14 (40%)
Type of drug associated with MRONJ
Zolendronate 17 (48.5%) *
Alendronate 9 (25.7%)
Denosumab 2 (5.7%)
Alendronate + Denosumab 2 (5.7%)
Alendronate + Risendronate 1(2.9%)
Alendronate + Zolendronate 1(2.9%)
Alendronate + Ibandronate 1(2.9%)
Ibandronate + Clodronate 1 (2.9%)
Zolendronate + Denosumab 1 (2.9%)
Stage of MRONJ
-Stage I 6 (17.1%)
-Stage II 28 (80%)
-Stage III 1 (2.9%) *
MRONJ localization
Maxilla 12 (34.2%)
Mandible 24 (68.5%) * ψ
* χ2 test, significance: p ≤ 0.05. ψ One patient had both mandibular and maxillary lesions.
antibiotics-10-00195-t002_Table 2 Table 2 Clinical data concerning MRONJ-related therapy.
MRONJ-Related Therapy Months
Duration of therapy
-Zoledronate 34.29 ± 33.42
-Alendronate 79.42 ± 63.33
-Denosumab 15 ± 7.94
Suspension of drug
-Zoledronate 8.53 ± 20.21
-Alendronate 13.15 ± 19.58
-Denosumab 0.8 ± 1.1
antibiotics-10-00195-t003_Table 3 Table 3 Clinical outcomes of patients who received pentoxifylline and tocopherol therapy for management of MRONJ.
Age (Years) Cause of Anti-Resorptive Treatment Gender Type of MRONJ-Related Drug UCONNS Score Stage of MRONJ Site of MRONJ Outcomes
68 Cancer Female Alendronate 12 Stage II Mandible Healed
65 Cancer Female Zoledronate 23 Stage II Mandible Worsened
53 Cancer Female Zoledronate 31 Stage II Mandible Stable
51 Cancer Female Zoledronate-Denosumab 24 Stage II Maxilla Worsened
93 Osteoporosis Female Alendronate-Denosumab 13 Stage II Maxilla/Mandible Healed
85 Cancer Female Zoledronate 26 Stage II Maxilla Healed
65 Cancer Male Denosumab 22 Stage II Mandible Healed
90 Osteoporosis Female Alendronate 8 Stage II Maxilla Healed
77 Cancer Male Zoledronate 21 Stage II Mandible Healed
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Oral | DrugAdministrationRoute | CC BY | 33671429 | 19,769,348 | 2021-02-17 |
What was the administration route of drug 'ALENDRONIC ACID'? | Conservative Management of Medication-Related Osteonecrosis of the Jaws (MRONJ): A Retrospective Cohort Study.
BACKGROUND
Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of bisphosphonates and anti-resorptive drugs prescribed for treatment of severe osteoporosis, Paget's disease, and bone malignancies. The aim of this study was to evaluate the clinical outcome of a combined pharmacological and surgical management strategy on patients affected by MRONJ.
METHODS
Medical records of patients with MRONJ were retrospectively examined to collect clinical history data. Conservative management included an initial pharmacological phase with antibiotics and antiseptic agents, followed by surgical intervention to remove bone sequestrum. Primary outcomes were healing from MRONJ at short term (1 month after surgery) and at longer term (3 months after surgery). Secondary outcome was assessment of recurrences at longer-term follow-up.
RESULTS
Thirty-five patients were included in the study with mean follow-up of 23.86 ± 18.14 months. Seven cases showed spontaneous exfoliation of necrotic bone during pharmacological therapy, which in one case did not require any further intervention. At 1-month posttreatment, 31 out of 35 (88.5%) patients showed complete healing. The 25 patients who were followed for at least 3 months revealed a healing rate of 92% (23/25). Recurrences occurred in 7 patients out 23 who showed the long-term healing, after a mean period of 7.29 ± 3.45 months. The prognostic score (University of Connecticut Osteonecrosis Numerical Scale-UCONNS) was significantly higher (p = 0.01) in patients with poor healing as compared to complete healing, both at 1 and 3 months posttreatment.
CONCLUSIONS
A MRONJ treatment approach based on a combined pharmacological and surgical treatment strategy showed a high rate of healing and few recurrences.
1. Introduction
As defined in 2014 by the American Association of Oral and Maxillofacial Surgeons (AAOMS), medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of bisphosphonates and of certain anti-resorptive drugs, such as denosumab [1], commonly prescribed for controlling severe osteoporosis, Paget’s disease, and bone malignancies, including multiple myeloma and bone metastases [1]. Bisphosphonates (BPs) are analogues of inorganic pyrophosphate, inhibiting the pyrophosphate-dependent enzymes mediating bone resorption [2]. Denosumab is a human monoclonal immunoglobulin G2 subclass (IgG2) that mimics the function of the endogenous molecule osteoprotegerin (OPG), reducing bone metabolism [3]. Even if the potential of BPs and denosumab to increase the survival in cancer patients remains uncertain, they significantly improve the quality of life, reducing bone pain in cases of advanced bone metastases [4].
MRONJ pathogenesis is still largely unknown. A multi-factorial mechanism has been advocated, involving inhibition of angiogenesis and remodeling in bone tissue, presence of continuous micro-trauma within the oral cavity during eating and speaking, as well as a potential role and impact from oral mucosal inflammation or odontogenic infection [5,6].
A recognized risk factor for MRONJ is high concentration and long duration of BP intake [7]. The frequency of MRONJ in cancer patients has been estimated, ranging from 1% to 15%, while the frequency in patients with osteoporosis, receiving much lower BP doses, is estimated around 0.001% to 0.01% [8,9]. Antiangiogenic agents, tyrosine kinase inhibitors, and monoclonal antibody-targeting Vascular-Endothelial Growth Factor (VEGF)—such as sunitimib, sorafefenib, bevacizumab—worsen the risk of MRONJ from 5- to 10-fold [1,10]. Since MRONJ negatively impacts patient quality of life [11], preventive dental treatment is strongly recommended [12].
Despite no international consensus for treating MRONJ, a decisional tree to manage these patients requires consideration of the staging of MRONJ, patient age, gender, and systemic health [9]. The primary objective of treatment is to control symptoms, mainly pain, and to avoid progression of MRONJ to a more advanced stage [13]. Recent studies suggest a need for early surgical management to ensure complete removal of the necrotic bone following implementation of a first-line conservative nonsurgical approach with antibiotics, antimicrobials, and analgesics [13,14,15,16,17]. Surgery, in particular, is recommended in the presence of well-defined bone sequestra; in these cases, sequestrectomy or surgical debridement is needed. In patients with advanced stages who show a progression of the disease, or in cases of persistent pain and infection despite the medical therapy, an extensive resection is required [1,18,19]. Medical therapy itself appears to control pain and infection in about 50% of patients. A risk of sepsis, mainly in immunocompromised cancer patients, further justifies surgical intervention [19]. To date, MRONJ surgical therapy has been associated with variable percentages of success due to high heterogeneity among published studies [18,20,21].
The aim of this study was to retrospectively assess the success and recurrence rates in a cohort of MRONJ patients treated with a first pharmacological phase, intended for isolating gradually necrotic bone tissue and promoting sequestration, followed by a surgical intervention limiting the need for extensive resections.
2. Materials and Methods
2.1. Patients
2.1.1. Study Design and Patient Population
This cohort study retrospectively analyzed clinical records of MRONJ patients referred to the Oral Medicine Unit (ASST Santi Paolo e Carlo) at University of Milan, from October 2008 to December 2017. MRONJ staging of affected patients was defined according to 2014 AAOMS criteria [1].
2.1.2. Eligibility Criteria
The inclusion criteria included patients with MRONJ diagnosis at stage I–III, according to AAOMS criteria [1,21]. All patients were treated first with a pharmacological phase and then a surgical phase for bone sequestration removal [1,13,14,15,16,17]. The exclusion criteria were [1]: history of radiation therapy to the jaws or obvious metastatic disease to the jaws, no history of pharmacological therapy for MRONJ, and no history of surgical removal or spontaneous exfoliation of bone sequestra.
2.1.3. Treatment Intervention
Each patient received two phases of management, i.e., a pharmacological phase and a surgical phase. Based on previous literature [1,13,14,15,16,17], the protocol first used a medical management approach with antibiotics and local measures and followed the patients until there was evidence of bone sequester formation. At that point, surgical treatment of the MRONJ lesion site was performed with the goal of removing the sequestered bone and debridement of the site. In recurrent cases, the patients were referred to maxillofacial surgeons for major surgical procedures, i.e., bone resection.
Based on previous studies [1,9,21,22], systemic antibiotics were prescribed to all study patients as follows: amoxicillin 3 g/day or clindamycin 1800 mg/day in cases of allergy to the penicillin; for the cases scarcely responsive to single-antibiotic therapy, metronidazole 500 mg/day for a maximum 14 days. Topical antiseptic therapy with 0.2% chlorhexidine mouthwash and 1% chlorhexidine gel, applied onto exposed necrotic bone, was also prescribed [17].
Surgical intervention (sequestrectomy) was performed when sequestered bone was clinically or radiographically evident and not spontaneously exfoliated, following a MRONJ protocol previously recommended [23]. Briefly, one week before surgical intervention, each patient received the dental scaling, topical antiseptic therapy (0.2% chlorhexidine mouthwash, twice/day), and the prescription of antibiotic therapy started three days before the surgery (amoxicillin 3 g/day, or clindamycin 1800 mg/day in case of allergy to penicillin) [23]. On the day of surgical intervention, under local anesthesia, necrotic bone was removed via full-thickness mucoperiosteal flap, with minimal trauma to the cortical plates. Teeth involved in the necrotic area were extracted and a meticulous bone curettage and osteoplasty were performed until clear bleeding and white vital bone were clinically evident. The flap was closed with an absorbable suture via periosteal releasing incisions to achieve primary closure and in order to maximize the vascular supply to the area as well as to reduce risk of infection at the surgical site. Post-surgery, patients continued for two weeks the systemic antibiotic therapy and antiseptic mouthwash and also applied 1% chlorhexidine gel onto the surgical wound twice/day for at least 14 days. On the basis of the promising results obtained in previous studies [24,25,26], and under approval of the patient’s oncologist, pentoxifylline and tocopherol were also prescribed per os (pentoxifylline 800 mg/day + tocopherol 800 U.I./day), before and/or after surgical intervention, according to clinical case.
2.2. Data Collection
Clinical and demographic data collected for each patient included, age, gender, systemic conditions, MRONJ stage [1], bisphosphonate, anti-resorptive, or anti-angiogenetic therapy (dosage, suspension, and duration), formation of bone sequestra, area of exposed bone (localization and size), date of surgical intervention(s), number of recurrences, and length of follow-up. The duration of therapy was determined as the period from the start of treatment to the first visit to our clinical unit. The prognostic score (University of Connecticut Osteonecrosis Numerical Scale—UCONNS) described by Landesberg was applied to find possible correlation between outcomes and patient systemic conditions [27]. UCONNS scores assess the individual prognosis based on known risk factors for MRONJ management failure, including systemic health conditions, comorbidities, type, and duration of bisphosphonate therapy and type of intervention performed. UCONNS scores were categorized as follow: 0–8, 9–16, 17–24, 25–32.
2.3. Outcomes
2.3.1. Primary Outcomes: Clinical Healing
The following criteria for clinical healing were used (adapted from [28]):Short-term healing—A patient was defined as “healed at short-term”, if presenting, for at least 1 month after sequestrectomy or spontaneous exfoliation of necrotic bone, the following clinical picture: absence of exposed necrotic bone or bone that can be probed through a fistula; absence of purulent drainage; absence of edema and stimulated pain; complete mucosal coverage of the surgical site.
Long-term healing—A patient was defined as “healed at long-term”, if presenting the same clinical picture described above but lasting for at least 3 months after sequestrectomy or spontaneous exfoliation of bone sequestration.
Stable MRONJ clinical picture—A patient was “stable” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with the same stage seen during the first visit.
Worsened MRONJ clinical picture—A patient was “worsened” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with a worse stage than found at first diagnosis.
Improved MRONJ clinical picture—A patient was “improved” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with a better stage than the one of the first diagnosis.
2.3.2. Secondary Outcomes: Rate of MRONJ Recurrence
Recurrence
Recurrence was defined as the appearance of exposed necrotic bone or bone that could be probed through a fistula, in association or not with radiographic evidence of architectural bone changes persisting for more than 8 weeks in an area that had already demonstrated a long-term healing.
Adverse Effects
Any adverse events due to pharmacological and/or surgical phases were recorded when specified in the medical record.
2.4. Statistical Analysis
Means and standard deviations were calculated for continuous variables; Kolmogorov–Smirnov test of normality was applied, and data were normally distributed. A t-test was used to compare means between two unpaired samples. For categorical variables, extracted data were expressed as percentages, and statistical analyses to identify significant differences were performed by applying the χ2 test using the online Graphpad statistical software (GraphPad Software®, San Diego, CA, USA). Statistical significance was set at p ≤ 0.05. Odds ratios were also calculated using the online MedCalc Software Ltd statistical software (MedCalc Software Ltd., Ostend, Belgium).
2.5. Ethical Approval
The study was performed under ethical approval obtained from the Ethic Committee of the AO San Paolo (ID study approval: ONM-BF-Gene, 2016). Opt-out patient consent was obtained.
2.6. STROBE Statement
The Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement was used to prepare this report.
3. Results
From an initial cohort of 45 patients with MRONJ, 35 subjects were included in the study. Ten patients were excluded for the following reasons: positive anamnesis for head and neck radiotherapy (n = 2), or insufficient clinical data (n = 8). Figure 1 provides a flow-chart of enrolled study patients, while patient demographic and clinical data are summarized in Table 1.
Most of patients were women (χ2; p = 0.02); the mean age of study participants at the first examination was 73.46 ± 9.29 years (range 51–93 years) (Table 1). Six patients out thirty-five were undergoing anticancer chemotherapy at the moment of surgical intervention. Eight patients were receiving intravenous steroid treatment, which in four cases was associated with the chemotherapeutic regimen (Table 1). Six patients were also affected by diabetes.
Most patients were treated with zoledronate and showed stage II MRONJ lesions (Table 1).
The mean follow-up of patients, from the first visit up to the last one available, was 23.86 ± 18.14 months (range: 1–74 months). The mean therapy with zoledronate lasted 34.29 ± 33.42 months; in some cases, the drug was suspended for a mean period of 8.53 ± 20.21 months. The mean duration of alendronate therapy was longer (79.42 ± 63.33 months), with a mean suspension period, when occurring, of 13.15 ± 19.58 months. The mean duration of the therapy with denosumab was shorter, lasting 15 ± 7.94 months, with a mean suspension time of 0.8 ± 1.1 months (Table 2).
The pharmacological phase involved the use of topical chlorhexidine and systemic amoxicillin, with 11 patients also receiving metronidazole. In nine patients (25.71%), the supportive pharmacological therapy for MRONJ included also pentoxifylline and tocopherol (mean period of administration 3.81 ± 2.46 months).
Seven cases showed spontaneous exfoliation of necrotic bone. In four cases, the exfoliation occurred during the pharmacological phase: in one case, the sequestrum was completely exfoliated not requiring any further intervention, while in three patients the sequestra were partially exfoliated, requiring the further surgical intervention at the same site. In the other three patients, a spontaneous exfoliation of an additional bone sequestrum followed sequestrectomy.
Fifty-seven interventions of sequestrectomy were performed. Eighteen patients received a single surgical intervention, while four patients underwent two interventions in two different sites affected by MRONJ. In five subjects, the interventions were more than two; one patient required five interventions at the same site.
Figure 2 describes a clinical case where antibiotic administration gradually resulted in the isolation of bone sequestrum from the surrounding healthy bone.
Figure 3A–F describes the surgical intervention for bone sequestrum removal in a patient who developed MRONJ after zolendronate intake for oncological reasons (metastases of breast carcinoma).
3.1. Primary Outcomes
3.1.1. Short-Term Healing
At 1-month post-surgery, 31 out 35 (88.57%) patients showed complete healing. The four not-healed cases were MRONJ stage II: in two cases the picture was stable at last follow-up, while the other two demonstrated a worsening of their conditions. These four patients received zolendronate (in one case alternating to denosumab) for oncological reasons for a mean period of 18.66 ± 4.72 months (range 17–60 months). Two of them had suspended the drug for 10 and 13 months. The mean UCONNS prognostic score was 15.83 ± 7.24 in healed patients, 25 ± 4.08 in not-healed patients (t-test, p = 0.01). Figure 4 describes the short-term healing outcomes depending on UCONNS score.
3.1.2. Long-Term Healing
Twenty-five patients had long-term follow-up (at least 3 months), while the other ten patients, including two patients who did not heal at short-term, were lost prior to further follow-up. In the 25 patients, the mean follow-up was 27.28 ± 15.37 months from the first visit. Twenty-three out 25 (92%) showed complete healing of the surgical site for at least 3 months after surgery (Figure 5). Two patients were not healed at either short-term or long-term follow-up. One of them showed a stable MRONJ lesion in the posterior maxilla, while the other patient with MRONJ at the mandible showed a worsening clinical picture. This patient was referred to maxillofacial surgeons for major surgery. Both not-healed patients had MRONJ stage II and received zoledronate for oncological reasons, respectively for 24 and 17 months. One of the patients was under current zoledronate treatment (in addition to chemotherapy), while the other patient had suspended the drug 13 months before. The mean UCONNS prognostic score was 16.56 ± 7.63 in healed patients, as compared to 22.5 ± 0.7 in not-healed patients (t-test, p = 0.001).
Table 3 reports healing outcomes at long term in patients who received also pentoxifylline and tocopherol therapy.
3.2. Secondary Outcomes
3.2.1. Recurrences
Recurrences were recorded in seven patients out 23 (30.4%) who showed long-term healing: two were stage I, four at stage II, and one was at stage III. The recurrences occurred on average 7.29 ± 3.45 months after surgical intervention. Five out of seven patients who showed recurrences were receiving zoledronate for a mean period of 37.2 ± 24.47 months, while the remaining two patients were under therapy with alendronate for a mean period of 84 ± 16.97 months (Odds Ratio—OR:1.81; 95% CI: 0.27 to 11.86; p = 0.53). Recurrence in the oncological group occurred in five out 15 healed patients, while considering the osteoporotic group in 2 out 8 healed patients (OR 1. 50; 95% CI: 0.21 to 10.30; p = 0.68) (Figure 6).
3.2.2. Adverse Events
No adverse events were reported, except for one case of spontaneous bleeding from the exposed necrotic bone, which occurred soon after the start of pentoxifylline and tocopherol therapy.
4. Discussion
MRONJ is a debilitating condition that more frequently affects females, the elderly, and persons treated for oncological reasons [18,20,28]. Although this complication has important clinical implications for dental practitioners—who need to know the correct management of a patient under anti-resorptive therapy—recent studies highlighted a lack of knowledge among dentists and dental students [29,30,31].
These findings support that, following a combined pharmacological and surgical conservative approach, most patients experience a complete healing. The UCONNS prognostic score was significantly higher in patients with poor healing as compared to those with complete healing in lesions. This conservative approach of MRONJ management was based on previous study outcomes [1,9,21,22] and included systemic antibiotics as well as antiseptic therapy with 0.2% chlorhexidine mouthwash and 1% chlorhexidine gel applied onto exposed necrotic bone [17].
Treatment of MRONJ patients remains challenging, and therapeutic options vary from pharmacological supportive approach with antibiotics and antiseptics to extensive surgical resection of necrotic bone. According to previous studies [14,18,20,32,33], an early surgical approach with appropriate resection margins and primary wound closure can ensure a better surgical outcome (mucosal healing without signs of infection) stage improvement at 6 months, with mucosal and radiographic healing evident at one-year posttreatment. Since pharmacological therapy alone rarely leads to lesion healing even at stage I [16], Khan and colleagues [9], in their systematic review, recommended surgical resection with tension-free primary closure.
In our experience, pharmacological management of MRONJ lesions seems to promote progressive isolation of the bone sequestrum, enabling minimally invasive surgical intervention, with a potentially higher rate of long-term success than major surgical resection. Progressive isolation of necrotic bone throughout the preliminary pharmacologic phase allows removal of necrotic tissue without undue sacrifice of healthy bone.
Consistent with previous research findings on conservative management of MRONJ [16,17,21], a high healing rate was achieved in the present study, although the study sample size was small. Importantly, UCONNS scores were confirmed to play a significant role in influencing treatment outcomes. Indeed, similar to a proposed cut-off value of UCONNS scores ≥ 15 to identify a higher rate of therapeutic failure [34], we found that all non-healed (both stable and worse) patients had a UCONNS score beyond 17.
The rate of recurrence after 3-month healing (30.4%), in the present study, appeared similar to that reported by Mucke and colleagues (28.7%), although they performed only surgical debridement in most of their patients [32]. However, due to methodological heterogeneity, a direct comparison among studies remains still complicated, considering that recurrence may occur after several months and that a too short follow-up period may bias the findings.
The additional use of pentoxifylline and tocopherol in treatment of MRONJ lesions is worth further investigation. In this study, most patients healed without major adverse side effects. Only one patient experienced bleeding at the start of pentoxifylline and tocopherol therapy. The Italian drug agency (AIFA) [35] warned of excessive bleeding among patients receiving anticoagulants, thrombolytic agents, and inhibitors of platelet aggregation who simultaneously are administered pentoxifylline and tocopherol. In our study the patient who developed spontaneous bleeding was not under treatment with any of these drugs.
The main limitation of this retrospective study is the use of medical records not specifically designed for the aim of the study. Thus, collected data might be limited in scope, making identification of potential confounding factors difficult, and making patient inclusion into the study prone to selection bias. Further limitations include varying lengths of follow-up of patients and varying patient compliance with the pharmacological protocol, along with the lack of calibration among the oral surgeons who performed the interventions and a lack of standardization in data collection. The retrospective design also predisposes the study to numerous threats to external validity, which limits interpretation and generalizability of the results (such as single-group threat, i.e., the lack of a comparison and/or control groups, and historical threat, where other events, different from the intervention under investigation, can affect the outcomes) [36].
5. Conclusions
An initial pharmacological phase based on antibiotic and antiseptic agents is useful to gradually isolate bone sequestration in MRONJ patients and facilitate a subsequent surgical phase. This approach is particularly advisable for treatment of stages I and II of MRONJ. UCONNS-related prognostic factors play a relevant role in determining the success of MRONJ therapy.
Author Contributions
Conceptualization, G.L. and E.M.V.; methodology, E.M.V., G.L. and N.L.; validation, G.L. and A.S.; formal analysis, G.L. and E.M.V.; investigation, N.L., A.P. and G.V.; data curation, N.L., G.V. and A.P.; writing—original draft preparation, G.V. and E.M.V.; writing—review and editing, N.L. and G.L.; supervision, G.L. and A.S. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of AO San Paolo (ID protocol approval: ONM-BF-Gene, 2016).
Informed Consent Statement
This study is retrospective study. Opt-out patient consent was obtained.
Data Availability Statement
The data presented in this study are available on request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Flow diagram of enrolled patients.
Figure 2 Clinical case of MRONJ localized in left mandible. (A) Cone beam computed tomography (CBCT) images, sagittal and frontal views, showing isolation of mandibular bone sequestration following antibiotic and topical antiseptic therapy (red arrows indicate the bone sequestrum). (B) Necrotic bone sequestration, resulting from the surgical intervention.
Figure 3 Clinical case of MRONJ localized in the upper maxilla. (A) Cone beam computed tomography (CBCT) images, frontal and sagittal views, showing maxillary bone sequestration (red arrows indicate the bone sequestrum). (B) Intraoral clinical view showing the presence of fistula, which demonstrates the presence of infection. (C) Necrotic bone sequestrum removal, after the opening of the surgical flap (mid-crestal incision on the alveolar crest of the edentulous area). (D) The necrotic bone was completely removed until reaching the healthy bone tissue; bone curettage and osteoplasty were performed until vital bone was clinically observed. (E) Primary closure via periosteal releasing incisions using absorbable suture. (F) Follow-up after 3 months from the surgical intervention showing a complete tissue healing.
Figure 4 Comparison of the short-term healing outcomes depending on University of Connecticut Osteonecrosis Numerical Scale (UCONNS) score.
Figure 5 Comparison of the long-term healing outcomes depending on UCONNS score.
Figure 6 Comparison of long-term healing and recurrence in oncological and osteoporotic group.
antibiotics-10-00195-t001_Table 1 Table 1 Demographic and clinical data concerning patient gender, age, comorbidities, concomitant cancer therapies, stage, and localization of medication-related osteonecrosis of the jaw (MRONJ) (n = 35).
Demographic and Clinical Data Number of Patients (%)
Gender
-Male 11 (31.4%)
-Female 24 (68.6%) *
Age, years Years
Range 51–93
Mean, SD 73.46 ± 9.29
Concomitant cancer therapies
-Steroids 4 (11.4%)
-Chemotherapy 6 (17.1%)
-Steroids and Chemotherapy 4 (11.4%)
-No steroids, No Chemotherapy 21 (60%)
Primary disease requiring anti-resorptive drugs
-Breast cancer 10 (28.6%)
-Prostate cancer 4 (11.4%)
-Multiple myeloma 7 (20%)
-Osteoporosis 14 (40%)
Type of drug associated with MRONJ
Zolendronate 17 (48.5%) *
Alendronate 9 (25.7%)
Denosumab 2 (5.7%)
Alendronate + Denosumab 2 (5.7%)
Alendronate + Risendronate 1(2.9%)
Alendronate + Zolendronate 1(2.9%)
Alendronate + Ibandronate 1(2.9%)
Ibandronate + Clodronate 1 (2.9%)
Zolendronate + Denosumab 1 (2.9%)
Stage of MRONJ
-Stage I 6 (17.1%)
-Stage II 28 (80%)
-Stage III 1 (2.9%) *
MRONJ localization
Maxilla 12 (34.2%)
Mandible 24 (68.5%) * ψ
* χ2 test, significance: p ≤ 0.05. ψ One patient had both mandibular and maxillary lesions.
antibiotics-10-00195-t002_Table 2 Table 2 Clinical data concerning MRONJ-related therapy.
MRONJ-Related Therapy Months
Duration of therapy
-Zoledronate 34.29 ± 33.42
-Alendronate 79.42 ± 63.33
-Denosumab 15 ± 7.94
Suspension of drug
-Zoledronate 8.53 ± 20.21
-Alendronate 13.15 ± 19.58
-Denosumab 0.8 ± 1.1
antibiotics-10-00195-t003_Table 3 Table 3 Clinical outcomes of patients who received pentoxifylline and tocopherol therapy for management of MRONJ.
Age (Years) Cause of Anti-Resorptive Treatment Gender Type of MRONJ-Related Drug UCONNS Score Stage of MRONJ Site of MRONJ Outcomes
68 Cancer Female Alendronate 12 Stage II Mandible Healed
65 Cancer Female Zoledronate 23 Stage II Mandible Worsened
53 Cancer Female Zoledronate 31 Stage II Mandible Stable
51 Cancer Female Zoledronate-Denosumab 24 Stage II Maxilla Worsened
93 Osteoporosis Female Alendronate-Denosumab 13 Stage II Maxilla/Mandible Healed
85 Cancer Female Zoledronate 26 Stage II Maxilla Healed
65 Cancer Male Denosumab 22 Stage II Mandible Healed
90 Osteoporosis Female Alendronate 8 Stage II Maxilla Healed
77 Cancer Male Zoledronate 21 Stage II Mandible Healed
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Oral | DrugAdministrationRoute | CC BY | 33671429 | 19,071,547 | 2021-02-17 |
What was the administration route of drug 'CHLORHEXIDINE'? | Conservative Management of Medication-Related Osteonecrosis of the Jaws (MRONJ): A Retrospective Cohort Study.
BACKGROUND
Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of bisphosphonates and anti-resorptive drugs prescribed for treatment of severe osteoporosis, Paget's disease, and bone malignancies. The aim of this study was to evaluate the clinical outcome of a combined pharmacological and surgical management strategy on patients affected by MRONJ.
METHODS
Medical records of patients with MRONJ were retrospectively examined to collect clinical history data. Conservative management included an initial pharmacological phase with antibiotics and antiseptic agents, followed by surgical intervention to remove bone sequestrum. Primary outcomes were healing from MRONJ at short term (1 month after surgery) and at longer term (3 months after surgery). Secondary outcome was assessment of recurrences at longer-term follow-up.
RESULTS
Thirty-five patients were included in the study with mean follow-up of 23.86 ± 18.14 months. Seven cases showed spontaneous exfoliation of necrotic bone during pharmacological therapy, which in one case did not require any further intervention. At 1-month posttreatment, 31 out of 35 (88.5%) patients showed complete healing. The 25 patients who were followed for at least 3 months revealed a healing rate of 92% (23/25). Recurrences occurred in 7 patients out 23 who showed the long-term healing, after a mean period of 7.29 ± 3.45 months. The prognostic score (University of Connecticut Osteonecrosis Numerical Scale-UCONNS) was significantly higher (p = 0.01) in patients with poor healing as compared to complete healing, both at 1 and 3 months posttreatment.
CONCLUSIONS
A MRONJ treatment approach based on a combined pharmacological and surgical treatment strategy showed a high rate of healing and few recurrences.
1. Introduction
As defined in 2014 by the American Association of Oral and Maxillofacial Surgeons (AAOMS), medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of bisphosphonates and of certain anti-resorptive drugs, such as denosumab [1], commonly prescribed for controlling severe osteoporosis, Paget’s disease, and bone malignancies, including multiple myeloma and bone metastases [1]. Bisphosphonates (BPs) are analogues of inorganic pyrophosphate, inhibiting the pyrophosphate-dependent enzymes mediating bone resorption [2]. Denosumab is a human monoclonal immunoglobulin G2 subclass (IgG2) that mimics the function of the endogenous molecule osteoprotegerin (OPG), reducing bone metabolism [3]. Even if the potential of BPs and denosumab to increase the survival in cancer patients remains uncertain, they significantly improve the quality of life, reducing bone pain in cases of advanced bone metastases [4].
MRONJ pathogenesis is still largely unknown. A multi-factorial mechanism has been advocated, involving inhibition of angiogenesis and remodeling in bone tissue, presence of continuous micro-trauma within the oral cavity during eating and speaking, as well as a potential role and impact from oral mucosal inflammation or odontogenic infection [5,6].
A recognized risk factor for MRONJ is high concentration and long duration of BP intake [7]. The frequency of MRONJ in cancer patients has been estimated, ranging from 1% to 15%, while the frequency in patients with osteoporosis, receiving much lower BP doses, is estimated around 0.001% to 0.01% [8,9]. Antiangiogenic agents, tyrosine kinase inhibitors, and monoclonal antibody-targeting Vascular-Endothelial Growth Factor (VEGF)—such as sunitimib, sorafefenib, bevacizumab—worsen the risk of MRONJ from 5- to 10-fold [1,10]. Since MRONJ negatively impacts patient quality of life [11], preventive dental treatment is strongly recommended [12].
Despite no international consensus for treating MRONJ, a decisional tree to manage these patients requires consideration of the staging of MRONJ, patient age, gender, and systemic health [9]. The primary objective of treatment is to control symptoms, mainly pain, and to avoid progression of MRONJ to a more advanced stage [13]. Recent studies suggest a need for early surgical management to ensure complete removal of the necrotic bone following implementation of a first-line conservative nonsurgical approach with antibiotics, antimicrobials, and analgesics [13,14,15,16,17]. Surgery, in particular, is recommended in the presence of well-defined bone sequestra; in these cases, sequestrectomy or surgical debridement is needed. In patients with advanced stages who show a progression of the disease, or in cases of persistent pain and infection despite the medical therapy, an extensive resection is required [1,18,19]. Medical therapy itself appears to control pain and infection in about 50% of patients. A risk of sepsis, mainly in immunocompromised cancer patients, further justifies surgical intervention [19]. To date, MRONJ surgical therapy has been associated with variable percentages of success due to high heterogeneity among published studies [18,20,21].
The aim of this study was to retrospectively assess the success and recurrence rates in a cohort of MRONJ patients treated with a first pharmacological phase, intended for isolating gradually necrotic bone tissue and promoting sequestration, followed by a surgical intervention limiting the need for extensive resections.
2. Materials and Methods
2.1. Patients
2.1.1. Study Design and Patient Population
This cohort study retrospectively analyzed clinical records of MRONJ patients referred to the Oral Medicine Unit (ASST Santi Paolo e Carlo) at University of Milan, from October 2008 to December 2017. MRONJ staging of affected patients was defined according to 2014 AAOMS criteria [1].
2.1.2. Eligibility Criteria
The inclusion criteria included patients with MRONJ diagnosis at stage I–III, according to AAOMS criteria [1,21]. All patients were treated first with a pharmacological phase and then a surgical phase for bone sequestration removal [1,13,14,15,16,17]. The exclusion criteria were [1]: history of radiation therapy to the jaws or obvious metastatic disease to the jaws, no history of pharmacological therapy for MRONJ, and no history of surgical removal or spontaneous exfoliation of bone sequestra.
2.1.3. Treatment Intervention
Each patient received two phases of management, i.e., a pharmacological phase and a surgical phase. Based on previous literature [1,13,14,15,16,17], the protocol first used a medical management approach with antibiotics and local measures and followed the patients until there was evidence of bone sequester formation. At that point, surgical treatment of the MRONJ lesion site was performed with the goal of removing the sequestered bone and debridement of the site. In recurrent cases, the patients were referred to maxillofacial surgeons for major surgical procedures, i.e., bone resection.
Based on previous studies [1,9,21,22], systemic antibiotics were prescribed to all study patients as follows: amoxicillin 3 g/day or clindamycin 1800 mg/day in cases of allergy to the penicillin; for the cases scarcely responsive to single-antibiotic therapy, metronidazole 500 mg/day for a maximum 14 days. Topical antiseptic therapy with 0.2% chlorhexidine mouthwash and 1% chlorhexidine gel, applied onto exposed necrotic bone, was also prescribed [17].
Surgical intervention (sequestrectomy) was performed when sequestered bone was clinically or radiographically evident and not spontaneously exfoliated, following a MRONJ protocol previously recommended [23]. Briefly, one week before surgical intervention, each patient received the dental scaling, topical antiseptic therapy (0.2% chlorhexidine mouthwash, twice/day), and the prescription of antibiotic therapy started three days before the surgery (amoxicillin 3 g/day, or clindamycin 1800 mg/day in case of allergy to penicillin) [23]. On the day of surgical intervention, under local anesthesia, necrotic bone was removed via full-thickness mucoperiosteal flap, with minimal trauma to the cortical plates. Teeth involved in the necrotic area were extracted and a meticulous bone curettage and osteoplasty were performed until clear bleeding and white vital bone were clinically evident. The flap was closed with an absorbable suture via periosteal releasing incisions to achieve primary closure and in order to maximize the vascular supply to the area as well as to reduce risk of infection at the surgical site. Post-surgery, patients continued for two weeks the systemic antibiotic therapy and antiseptic mouthwash and also applied 1% chlorhexidine gel onto the surgical wound twice/day for at least 14 days. On the basis of the promising results obtained in previous studies [24,25,26], and under approval of the patient’s oncologist, pentoxifylline and tocopherol were also prescribed per os (pentoxifylline 800 mg/day + tocopherol 800 U.I./day), before and/or after surgical intervention, according to clinical case.
2.2. Data Collection
Clinical and demographic data collected for each patient included, age, gender, systemic conditions, MRONJ stage [1], bisphosphonate, anti-resorptive, or anti-angiogenetic therapy (dosage, suspension, and duration), formation of bone sequestra, area of exposed bone (localization and size), date of surgical intervention(s), number of recurrences, and length of follow-up. The duration of therapy was determined as the period from the start of treatment to the first visit to our clinical unit. The prognostic score (University of Connecticut Osteonecrosis Numerical Scale—UCONNS) described by Landesberg was applied to find possible correlation between outcomes and patient systemic conditions [27]. UCONNS scores assess the individual prognosis based on known risk factors for MRONJ management failure, including systemic health conditions, comorbidities, type, and duration of bisphosphonate therapy and type of intervention performed. UCONNS scores were categorized as follow: 0–8, 9–16, 17–24, 25–32.
2.3. Outcomes
2.3.1. Primary Outcomes: Clinical Healing
The following criteria for clinical healing were used (adapted from [28]):Short-term healing—A patient was defined as “healed at short-term”, if presenting, for at least 1 month after sequestrectomy or spontaneous exfoliation of necrotic bone, the following clinical picture: absence of exposed necrotic bone or bone that can be probed through a fistula; absence of purulent drainage; absence of edema and stimulated pain; complete mucosal coverage of the surgical site.
Long-term healing—A patient was defined as “healed at long-term”, if presenting the same clinical picture described above but lasting for at least 3 months after sequestrectomy or spontaneous exfoliation of bone sequestration.
Stable MRONJ clinical picture—A patient was “stable” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with the same stage seen during the first visit.
Worsened MRONJ clinical picture—A patient was “worsened” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with a worse stage than found at first diagnosis.
Improved MRONJ clinical picture—A patient was “improved” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with a better stage than the one of the first diagnosis.
2.3.2. Secondary Outcomes: Rate of MRONJ Recurrence
Recurrence
Recurrence was defined as the appearance of exposed necrotic bone or bone that could be probed through a fistula, in association or not with radiographic evidence of architectural bone changes persisting for more than 8 weeks in an area that had already demonstrated a long-term healing.
Adverse Effects
Any adverse events due to pharmacological and/or surgical phases were recorded when specified in the medical record.
2.4. Statistical Analysis
Means and standard deviations were calculated for continuous variables; Kolmogorov–Smirnov test of normality was applied, and data were normally distributed. A t-test was used to compare means between two unpaired samples. For categorical variables, extracted data were expressed as percentages, and statistical analyses to identify significant differences were performed by applying the χ2 test using the online Graphpad statistical software (GraphPad Software®, San Diego, CA, USA). Statistical significance was set at p ≤ 0.05. Odds ratios were also calculated using the online MedCalc Software Ltd statistical software (MedCalc Software Ltd., Ostend, Belgium).
2.5. Ethical Approval
The study was performed under ethical approval obtained from the Ethic Committee of the AO San Paolo (ID study approval: ONM-BF-Gene, 2016). Opt-out patient consent was obtained.
2.6. STROBE Statement
The Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement was used to prepare this report.
3. Results
From an initial cohort of 45 patients with MRONJ, 35 subjects were included in the study. Ten patients were excluded for the following reasons: positive anamnesis for head and neck radiotherapy (n = 2), or insufficient clinical data (n = 8). Figure 1 provides a flow-chart of enrolled study patients, while patient demographic and clinical data are summarized in Table 1.
Most of patients were women (χ2; p = 0.02); the mean age of study participants at the first examination was 73.46 ± 9.29 years (range 51–93 years) (Table 1). Six patients out thirty-five were undergoing anticancer chemotherapy at the moment of surgical intervention. Eight patients were receiving intravenous steroid treatment, which in four cases was associated with the chemotherapeutic regimen (Table 1). Six patients were also affected by diabetes.
Most patients were treated with zoledronate and showed stage II MRONJ lesions (Table 1).
The mean follow-up of patients, from the first visit up to the last one available, was 23.86 ± 18.14 months (range: 1–74 months). The mean therapy with zoledronate lasted 34.29 ± 33.42 months; in some cases, the drug was suspended for a mean period of 8.53 ± 20.21 months. The mean duration of alendronate therapy was longer (79.42 ± 63.33 months), with a mean suspension period, when occurring, of 13.15 ± 19.58 months. The mean duration of the therapy with denosumab was shorter, lasting 15 ± 7.94 months, with a mean suspension time of 0.8 ± 1.1 months (Table 2).
The pharmacological phase involved the use of topical chlorhexidine and systemic amoxicillin, with 11 patients also receiving metronidazole. In nine patients (25.71%), the supportive pharmacological therapy for MRONJ included also pentoxifylline and tocopherol (mean period of administration 3.81 ± 2.46 months).
Seven cases showed spontaneous exfoliation of necrotic bone. In four cases, the exfoliation occurred during the pharmacological phase: in one case, the sequestrum was completely exfoliated not requiring any further intervention, while in three patients the sequestra were partially exfoliated, requiring the further surgical intervention at the same site. In the other three patients, a spontaneous exfoliation of an additional bone sequestrum followed sequestrectomy.
Fifty-seven interventions of sequestrectomy were performed. Eighteen patients received a single surgical intervention, while four patients underwent two interventions in two different sites affected by MRONJ. In five subjects, the interventions were more than two; one patient required five interventions at the same site.
Figure 2 describes a clinical case where antibiotic administration gradually resulted in the isolation of bone sequestrum from the surrounding healthy bone.
Figure 3A–F describes the surgical intervention for bone sequestrum removal in a patient who developed MRONJ after zolendronate intake for oncological reasons (metastases of breast carcinoma).
3.1. Primary Outcomes
3.1.1. Short-Term Healing
At 1-month post-surgery, 31 out 35 (88.57%) patients showed complete healing. The four not-healed cases were MRONJ stage II: in two cases the picture was stable at last follow-up, while the other two demonstrated a worsening of their conditions. These four patients received zolendronate (in one case alternating to denosumab) for oncological reasons for a mean period of 18.66 ± 4.72 months (range 17–60 months). Two of them had suspended the drug for 10 and 13 months. The mean UCONNS prognostic score was 15.83 ± 7.24 in healed patients, 25 ± 4.08 in not-healed patients (t-test, p = 0.01). Figure 4 describes the short-term healing outcomes depending on UCONNS score.
3.1.2. Long-Term Healing
Twenty-five patients had long-term follow-up (at least 3 months), while the other ten patients, including two patients who did not heal at short-term, were lost prior to further follow-up. In the 25 patients, the mean follow-up was 27.28 ± 15.37 months from the first visit. Twenty-three out 25 (92%) showed complete healing of the surgical site for at least 3 months after surgery (Figure 5). Two patients were not healed at either short-term or long-term follow-up. One of them showed a stable MRONJ lesion in the posterior maxilla, while the other patient with MRONJ at the mandible showed a worsening clinical picture. This patient was referred to maxillofacial surgeons for major surgery. Both not-healed patients had MRONJ stage II and received zoledronate for oncological reasons, respectively for 24 and 17 months. One of the patients was under current zoledronate treatment (in addition to chemotherapy), while the other patient had suspended the drug 13 months before. The mean UCONNS prognostic score was 16.56 ± 7.63 in healed patients, as compared to 22.5 ± 0.7 in not-healed patients (t-test, p = 0.001).
Table 3 reports healing outcomes at long term in patients who received also pentoxifylline and tocopherol therapy.
3.2. Secondary Outcomes
3.2.1. Recurrences
Recurrences were recorded in seven patients out 23 (30.4%) who showed long-term healing: two were stage I, four at stage II, and one was at stage III. The recurrences occurred on average 7.29 ± 3.45 months after surgical intervention. Five out of seven patients who showed recurrences were receiving zoledronate for a mean period of 37.2 ± 24.47 months, while the remaining two patients were under therapy with alendronate for a mean period of 84 ± 16.97 months (Odds Ratio—OR:1.81; 95% CI: 0.27 to 11.86; p = 0.53). Recurrence in the oncological group occurred in five out 15 healed patients, while considering the osteoporotic group in 2 out 8 healed patients (OR 1. 50; 95% CI: 0.21 to 10.30; p = 0.68) (Figure 6).
3.2.2. Adverse Events
No adverse events were reported, except for one case of spontaneous bleeding from the exposed necrotic bone, which occurred soon after the start of pentoxifylline and tocopherol therapy.
4. Discussion
MRONJ is a debilitating condition that more frequently affects females, the elderly, and persons treated for oncological reasons [18,20,28]. Although this complication has important clinical implications for dental practitioners—who need to know the correct management of a patient under anti-resorptive therapy—recent studies highlighted a lack of knowledge among dentists and dental students [29,30,31].
These findings support that, following a combined pharmacological and surgical conservative approach, most patients experience a complete healing. The UCONNS prognostic score was significantly higher in patients with poor healing as compared to those with complete healing in lesions. This conservative approach of MRONJ management was based on previous study outcomes [1,9,21,22] and included systemic antibiotics as well as antiseptic therapy with 0.2% chlorhexidine mouthwash and 1% chlorhexidine gel applied onto exposed necrotic bone [17].
Treatment of MRONJ patients remains challenging, and therapeutic options vary from pharmacological supportive approach with antibiotics and antiseptics to extensive surgical resection of necrotic bone. According to previous studies [14,18,20,32,33], an early surgical approach with appropriate resection margins and primary wound closure can ensure a better surgical outcome (mucosal healing without signs of infection) stage improvement at 6 months, with mucosal and radiographic healing evident at one-year posttreatment. Since pharmacological therapy alone rarely leads to lesion healing even at stage I [16], Khan and colleagues [9], in their systematic review, recommended surgical resection with tension-free primary closure.
In our experience, pharmacological management of MRONJ lesions seems to promote progressive isolation of the bone sequestrum, enabling minimally invasive surgical intervention, with a potentially higher rate of long-term success than major surgical resection. Progressive isolation of necrotic bone throughout the preliminary pharmacologic phase allows removal of necrotic tissue without undue sacrifice of healthy bone.
Consistent with previous research findings on conservative management of MRONJ [16,17,21], a high healing rate was achieved in the present study, although the study sample size was small. Importantly, UCONNS scores were confirmed to play a significant role in influencing treatment outcomes. Indeed, similar to a proposed cut-off value of UCONNS scores ≥ 15 to identify a higher rate of therapeutic failure [34], we found that all non-healed (both stable and worse) patients had a UCONNS score beyond 17.
The rate of recurrence after 3-month healing (30.4%), in the present study, appeared similar to that reported by Mucke and colleagues (28.7%), although they performed only surgical debridement in most of their patients [32]. However, due to methodological heterogeneity, a direct comparison among studies remains still complicated, considering that recurrence may occur after several months and that a too short follow-up period may bias the findings.
The additional use of pentoxifylline and tocopherol in treatment of MRONJ lesions is worth further investigation. In this study, most patients healed without major adverse side effects. Only one patient experienced bleeding at the start of pentoxifylline and tocopherol therapy. The Italian drug agency (AIFA) [35] warned of excessive bleeding among patients receiving anticoagulants, thrombolytic agents, and inhibitors of platelet aggregation who simultaneously are administered pentoxifylline and tocopherol. In our study the patient who developed spontaneous bleeding was not under treatment with any of these drugs.
The main limitation of this retrospective study is the use of medical records not specifically designed for the aim of the study. Thus, collected data might be limited in scope, making identification of potential confounding factors difficult, and making patient inclusion into the study prone to selection bias. Further limitations include varying lengths of follow-up of patients and varying patient compliance with the pharmacological protocol, along with the lack of calibration among the oral surgeons who performed the interventions and a lack of standardization in data collection. The retrospective design also predisposes the study to numerous threats to external validity, which limits interpretation and generalizability of the results (such as single-group threat, i.e., the lack of a comparison and/or control groups, and historical threat, where other events, different from the intervention under investigation, can affect the outcomes) [36].
5. Conclusions
An initial pharmacological phase based on antibiotic and antiseptic agents is useful to gradually isolate bone sequestration in MRONJ patients and facilitate a subsequent surgical phase. This approach is particularly advisable for treatment of stages I and II of MRONJ. UCONNS-related prognostic factors play a relevant role in determining the success of MRONJ therapy.
Author Contributions
Conceptualization, G.L. and E.M.V.; methodology, E.M.V., G.L. and N.L.; validation, G.L. and A.S.; formal analysis, G.L. and E.M.V.; investigation, N.L., A.P. and G.V.; data curation, N.L., G.V. and A.P.; writing—original draft preparation, G.V. and E.M.V.; writing—review and editing, N.L. and G.L.; supervision, G.L. and A.S. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of AO San Paolo (ID protocol approval: ONM-BF-Gene, 2016).
Informed Consent Statement
This study is retrospective study. Opt-out patient consent was obtained.
Data Availability Statement
The data presented in this study are available on request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Flow diagram of enrolled patients.
Figure 2 Clinical case of MRONJ localized in left mandible. (A) Cone beam computed tomography (CBCT) images, sagittal and frontal views, showing isolation of mandibular bone sequestration following antibiotic and topical antiseptic therapy (red arrows indicate the bone sequestrum). (B) Necrotic bone sequestration, resulting from the surgical intervention.
Figure 3 Clinical case of MRONJ localized in the upper maxilla. (A) Cone beam computed tomography (CBCT) images, frontal and sagittal views, showing maxillary bone sequestration (red arrows indicate the bone sequestrum). (B) Intraoral clinical view showing the presence of fistula, which demonstrates the presence of infection. (C) Necrotic bone sequestrum removal, after the opening of the surgical flap (mid-crestal incision on the alveolar crest of the edentulous area). (D) The necrotic bone was completely removed until reaching the healthy bone tissue; bone curettage and osteoplasty were performed until vital bone was clinically observed. (E) Primary closure via periosteal releasing incisions using absorbable suture. (F) Follow-up after 3 months from the surgical intervention showing a complete tissue healing.
Figure 4 Comparison of the short-term healing outcomes depending on University of Connecticut Osteonecrosis Numerical Scale (UCONNS) score.
Figure 5 Comparison of the long-term healing outcomes depending on UCONNS score.
Figure 6 Comparison of long-term healing and recurrence in oncological and osteoporotic group.
antibiotics-10-00195-t001_Table 1 Table 1 Demographic and clinical data concerning patient gender, age, comorbidities, concomitant cancer therapies, stage, and localization of medication-related osteonecrosis of the jaw (MRONJ) (n = 35).
Demographic and Clinical Data Number of Patients (%)
Gender
-Male 11 (31.4%)
-Female 24 (68.6%) *
Age, years Years
Range 51–93
Mean, SD 73.46 ± 9.29
Concomitant cancer therapies
-Steroids 4 (11.4%)
-Chemotherapy 6 (17.1%)
-Steroids and Chemotherapy 4 (11.4%)
-No steroids, No Chemotherapy 21 (60%)
Primary disease requiring anti-resorptive drugs
-Breast cancer 10 (28.6%)
-Prostate cancer 4 (11.4%)
-Multiple myeloma 7 (20%)
-Osteoporosis 14 (40%)
Type of drug associated with MRONJ
Zolendronate 17 (48.5%) *
Alendronate 9 (25.7%)
Denosumab 2 (5.7%)
Alendronate + Denosumab 2 (5.7%)
Alendronate + Risendronate 1(2.9%)
Alendronate + Zolendronate 1(2.9%)
Alendronate + Ibandronate 1(2.9%)
Ibandronate + Clodronate 1 (2.9%)
Zolendronate + Denosumab 1 (2.9%)
Stage of MRONJ
-Stage I 6 (17.1%)
-Stage II 28 (80%)
-Stage III 1 (2.9%) *
MRONJ localization
Maxilla 12 (34.2%)
Mandible 24 (68.5%) * ψ
* χ2 test, significance: p ≤ 0.05. ψ One patient had both mandibular and maxillary lesions.
antibiotics-10-00195-t002_Table 2 Table 2 Clinical data concerning MRONJ-related therapy.
MRONJ-Related Therapy Months
Duration of therapy
-Zoledronate 34.29 ± 33.42
-Alendronate 79.42 ± 63.33
-Denosumab 15 ± 7.94
Suspension of drug
-Zoledronate 8.53 ± 20.21
-Alendronate 13.15 ± 19.58
-Denosumab 0.8 ± 1.1
antibiotics-10-00195-t003_Table 3 Table 3 Clinical outcomes of patients who received pentoxifylline and tocopherol therapy for management of MRONJ.
Age (Years) Cause of Anti-Resorptive Treatment Gender Type of MRONJ-Related Drug UCONNS Score Stage of MRONJ Site of MRONJ Outcomes
68 Cancer Female Alendronate 12 Stage II Mandible Healed
65 Cancer Female Zoledronate 23 Stage II Mandible Worsened
53 Cancer Female Zoledronate 31 Stage II Mandible Stable
51 Cancer Female Zoledronate-Denosumab 24 Stage II Maxilla Worsened
93 Osteoporosis Female Alendronate-Denosumab 13 Stage II Maxilla/Mandible Healed
85 Cancer Female Zoledronate 26 Stage II Maxilla Healed
65 Cancer Male Denosumab 22 Stage II Mandible Healed
90 Osteoporosis Female Alendronate 8 Stage II Maxilla Healed
77 Cancer Male Zoledronate 21 Stage II Mandible Healed
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Topical | DrugAdministrationRoute | CC BY | 33671429 | 19,071,547 | 2021-02-17 |
What was the dosage of drug 'ALENDRONATE SODIUM'? | Conservative Management of Medication-Related Osteonecrosis of the Jaws (MRONJ): A Retrospective Cohort Study.
BACKGROUND
Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of bisphosphonates and anti-resorptive drugs prescribed for treatment of severe osteoporosis, Paget's disease, and bone malignancies. The aim of this study was to evaluate the clinical outcome of a combined pharmacological and surgical management strategy on patients affected by MRONJ.
METHODS
Medical records of patients with MRONJ were retrospectively examined to collect clinical history data. Conservative management included an initial pharmacological phase with antibiotics and antiseptic agents, followed by surgical intervention to remove bone sequestrum. Primary outcomes were healing from MRONJ at short term (1 month after surgery) and at longer term (3 months after surgery). Secondary outcome was assessment of recurrences at longer-term follow-up.
RESULTS
Thirty-five patients were included in the study with mean follow-up of 23.86 ± 18.14 months. Seven cases showed spontaneous exfoliation of necrotic bone during pharmacological therapy, which in one case did not require any further intervention. At 1-month posttreatment, 31 out of 35 (88.5%) patients showed complete healing. The 25 patients who were followed for at least 3 months revealed a healing rate of 92% (23/25). Recurrences occurred in 7 patients out 23 who showed the long-term healing, after a mean period of 7.29 ± 3.45 months. The prognostic score (University of Connecticut Osteonecrosis Numerical Scale-UCONNS) was significantly higher (p = 0.01) in patients with poor healing as compared to complete healing, both at 1 and 3 months posttreatment.
CONCLUSIONS
A MRONJ treatment approach based on a combined pharmacological and surgical treatment strategy showed a high rate of healing and few recurrences.
1. Introduction
As defined in 2014 by the American Association of Oral and Maxillofacial Surgeons (AAOMS), medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of bisphosphonates and of certain anti-resorptive drugs, such as denosumab [1], commonly prescribed for controlling severe osteoporosis, Paget’s disease, and bone malignancies, including multiple myeloma and bone metastases [1]. Bisphosphonates (BPs) are analogues of inorganic pyrophosphate, inhibiting the pyrophosphate-dependent enzymes mediating bone resorption [2]. Denosumab is a human monoclonal immunoglobulin G2 subclass (IgG2) that mimics the function of the endogenous molecule osteoprotegerin (OPG), reducing bone metabolism [3]. Even if the potential of BPs and denosumab to increase the survival in cancer patients remains uncertain, they significantly improve the quality of life, reducing bone pain in cases of advanced bone metastases [4].
MRONJ pathogenesis is still largely unknown. A multi-factorial mechanism has been advocated, involving inhibition of angiogenesis and remodeling in bone tissue, presence of continuous micro-trauma within the oral cavity during eating and speaking, as well as a potential role and impact from oral mucosal inflammation or odontogenic infection [5,6].
A recognized risk factor for MRONJ is high concentration and long duration of BP intake [7]. The frequency of MRONJ in cancer patients has been estimated, ranging from 1% to 15%, while the frequency in patients with osteoporosis, receiving much lower BP doses, is estimated around 0.001% to 0.01% [8,9]. Antiangiogenic agents, tyrosine kinase inhibitors, and monoclonal antibody-targeting Vascular-Endothelial Growth Factor (VEGF)—such as sunitimib, sorafefenib, bevacizumab—worsen the risk of MRONJ from 5- to 10-fold [1,10]. Since MRONJ negatively impacts patient quality of life [11], preventive dental treatment is strongly recommended [12].
Despite no international consensus for treating MRONJ, a decisional tree to manage these patients requires consideration of the staging of MRONJ, patient age, gender, and systemic health [9]. The primary objective of treatment is to control symptoms, mainly pain, and to avoid progression of MRONJ to a more advanced stage [13]. Recent studies suggest a need for early surgical management to ensure complete removal of the necrotic bone following implementation of a first-line conservative nonsurgical approach with antibiotics, antimicrobials, and analgesics [13,14,15,16,17]. Surgery, in particular, is recommended in the presence of well-defined bone sequestra; in these cases, sequestrectomy or surgical debridement is needed. In patients with advanced stages who show a progression of the disease, or in cases of persistent pain and infection despite the medical therapy, an extensive resection is required [1,18,19]. Medical therapy itself appears to control pain and infection in about 50% of patients. A risk of sepsis, mainly in immunocompromised cancer patients, further justifies surgical intervention [19]. To date, MRONJ surgical therapy has been associated with variable percentages of success due to high heterogeneity among published studies [18,20,21].
The aim of this study was to retrospectively assess the success and recurrence rates in a cohort of MRONJ patients treated with a first pharmacological phase, intended for isolating gradually necrotic bone tissue and promoting sequestration, followed by a surgical intervention limiting the need for extensive resections.
2. Materials and Methods
2.1. Patients
2.1.1. Study Design and Patient Population
This cohort study retrospectively analyzed clinical records of MRONJ patients referred to the Oral Medicine Unit (ASST Santi Paolo e Carlo) at University of Milan, from October 2008 to December 2017. MRONJ staging of affected patients was defined according to 2014 AAOMS criteria [1].
2.1.2. Eligibility Criteria
The inclusion criteria included patients with MRONJ diagnosis at stage I–III, according to AAOMS criteria [1,21]. All patients were treated first with a pharmacological phase and then a surgical phase for bone sequestration removal [1,13,14,15,16,17]. The exclusion criteria were [1]: history of radiation therapy to the jaws or obvious metastatic disease to the jaws, no history of pharmacological therapy for MRONJ, and no history of surgical removal or spontaneous exfoliation of bone sequestra.
2.1.3. Treatment Intervention
Each patient received two phases of management, i.e., a pharmacological phase and a surgical phase. Based on previous literature [1,13,14,15,16,17], the protocol first used a medical management approach with antibiotics and local measures and followed the patients until there was evidence of bone sequester formation. At that point, surgical treatment of the MRONJ lesion site was performed with the goal of removing the sequestered bone and debridement of the site. In recurrent cases, the patients were referred to maxillofacial surgeons for major surgical procedures, i.e., bone resection.
Based on previous studies [1,9,21,22], systemic antibiotics were prescribed to all study patients as follows: amoxicillin 3 g/day or clindamycin 1800 mg/day in cases of allergy to the penicillin; for the cases scarcely responsive to single-antibiotic therapy, metronidazole 500 mg/day for a maximum 14 days. Topical antiseptic therapy with 0.2% chlorhexidine mouthwash and 1% chlorhexidine gel, applied onto exposed necrotic bone, was also prescribed [17].
Surgical intervention (sequestrectomy) was performed when sequestered bone was clinically or radiographically evident and not spontaneously exfoliated, following a MRONJ protocol previously recommended [23]. Briefly, one week before surgical intervention, each patient received the dental scaling, topical antiseptic therapy (0.2% chlorhexidine mouthwash, twice/day), and the prescription of antibiotic therapy started three days before the surgery (amoxicillin 3 g/day, or clindamycin 1800 mg/day in case of allergy to penicillin) [23]. On the day of surgical intervention, under local anesthesia, necrotic bone was removed via full-thickness mucoperiosteal flap, with minimal trauma to the cortical plates. Teeth involved in the necrotic area were extracted and a meticulous bone curettage and osteoplasty were performed until clear bleeding and white vital bone were clinically evident. The flap was closed with an absorbable suture via periosteal releasing incisions to achieve primary closure and in order to maximize the vascular supply to the area as well as to reduce risk of infection at the surgical site. Post-surgery, patients continued for two weeks the systemic antibiotic therapy and antiseptic mouthwash and also applied 1% chlorhexidine gel onto the surgical wound twice/day for at least 14 days. On the basis of the promising results obtained in previous studies [24,25,26], and under approval of the patient’s oncologist, pentoxifylline and tocopherol were also prescribed per os (pentoxifylline 800 mg/day + tocopherol 800 U.I./day), before and/or after surgical intervention, according to clinical case.
2.2. Data Collection
Clinical and demographic data collected for each patient included, age, gender, systemic conditions, MRONJ stage [1], bisphosphonate, anti-resorptive, or anti-angiogenetic therapy (dosage, suspension, and duration), formation of bone sequestra, area of exposed bone (localization and size), date of surgical intervention(s), number of recurrences, and length of follow-up. The duration of therapy was determined as the period from the start of treatment to the first visit to our clinical unit. The prognostic score (University of Connecticut Osteonecrosis Numerical Scale—UCONNS) described by Landesberg was applied to find possible correlation between outcomes and patient systemic conditions [27]. UCONNS scores assess the individual prognosis based on known risk factors for MRONJ management failure, including systemic health conditions, comorbidities, type, and duration of bisphosphonate therapy and type of intervention performed. UCONNS scores were categorized as follow: 0–8, 9–16, 17–24, 25–32.
2.3. Outcomes
2.3.1. Primary Outcomes: Clinical Healing
The following criteria for clinical healing were used (adapted from [28]):Short-term healing—A patient was defined as “healed at short-term”, if presenting, for at least 1 month after sequestrectomy or spontaneous exfoliation of necrotic bone, the following clinical picture: absence of exposed necrotic bone or bone that can be probed through a fistula; absence of purulent drainage; absence of edema and stimulated pain; complete mucosal coverage of the surgical site.
Long-term healing—A patient was defined as “healed at long-term”, if presenting the same clinical picture described above but lasting for at least 3 months after sequestrectomy or spontaneous exfoliation of bone sequestration.
Stable MRONJ clinical picture—A patient was “stable” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with the same stage seen during the first visit.
Worsened MRONJ clinical picture—A patient was “worsened” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with a worse stage than found at first diagnosis.
Improved MRONJ clinical picture—A patient was “improved” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with a better stage than the one of the first diagnosis.
2.3.2. Secondary Outcomes: Rate of MRONJ Recurrence
Recurrence
Recurrence was defined as the appearance of exposed necrotic bone or bone that could be probed through a fistula, in association or not with radiographic evidence of architectural bone changes persisting for more than 8 weeks in an area that had already demonstrated a long-term healing.
Adverse Effects
Any adverse events due to pharmacological and/or surgical phases were recorded when specified in the medical record.
2.4. Statistical Analysis
Means and standard deviations were calculated for continuous variables; Kolmogorov–Smirnov test of normality was applied, and data were normally distributed. A t-test was used to compare means between two unpaired samples. For categorical variables, extracted data were expressed as percentages, and statistical analyses to identify significant differences were performed by applying the χ2 test using the online Graphpad statistical software (GraphPad Software®, San Diego, CA, USA). Statistical significance was set at p ≤ 0.05. Odds ratios were also calculated using the online MedCalc Software Ltd statistical software (MedCalc Software Ltd., Ostend, Belgium).
2.5. Ethical Approval
The study was performed under ethical approval obtained from the Ethic Committee of the AO San Paolo (ID study approval: ONM-BF-Gene, 2016). Opt-out patient consent was obtained.
2.6. STROBE Statement
The Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement was used to prepare this report.
3. Results
From an initial cohort of 45 patients with MRONJ, 35 subjects were included in the study. Ten patients were excluded for the following reasons: positive anamnesis for head and neck radiotherapy (n = 2), or insufficient clinical data (n = 8). Figure 1 provides a flow-chart of enrolled study patients, while patient demographic and clinical data are summarized in Table 1.
Most of patients were women (χ2; p = 0.02); the mean age of study participants at the first examination was 73.46 ± 9.29 years (range 51–93 years) (Table 1). Six patients out thirty-five were undergoing anticancer chemotherapy at the moment of surgical intervention. Eight patients were receiving intravenous steroid treatment, which in four cases was associated with the chemotherapeutic regimen (Table 1). Six patients were also affected by diabetes.
Most patients were treated with zoledronate and showed stage II MRONJ lesions (Table 1).
The mean follow-up of patients, from the first visit up to the last one available, was 23.86 ± 18.14 months (range: 1–74 months). The mean therapy with zoledronate lasted 34.29 ± 33.42 months; in some cases, the drug was suspended for a mean period of 8.53 ± 20.21 months. The mean duration of alendronate therapy was longer (79.42 ± 63.33 months), with a mean suspension period, when occurring, of 13.15 ± 19.58 months. The mean duration of the therapy with denosumab was shorter, lasting 15 ± 7.94 months, with a mean suspension time of 0.8 ± 1.1 months (Table 2).
The pharmacological phase involved the use of topical chlorhexidine and systemic amoxicillin, with 11 patients also receiving metronidazole. In nine patients (25.71%), the supportive pharmacological therapy for MRONJ included also pentoxifylline and tocopherol (mean period of administration 3.81 ± 2.46 months).
Seven cases showed spontaneous exfoliation of necrotic bone. In four cases, the exfoliation occurred during the pharmacological phase: in one case, the sequestrum was completely exfoliated not requiring any further intervention, while in three patients the sequestra were partially exfoliated, requiring the further surgical intervention at the same site. In the other three patients, a spontaneous exfoliation of an additional bone sequestrum followed sequestrectomy.
Fifty-seven interventions of sequestrectomy were performed. Eighteen patients received a single surgical intervention, while four patients underwent two interventions in two different sites affected by MRONJ. In five subjects, the interventions were more than two; one patient required five interventions at the same site.
Figure 2 describes a clinical case where antibiotic administration gradually resulted in the isolation of bone sequestrum from the surrounding healthy bone.
Figure 3A–F describes the surgical intervention for bone sequestrum removal in a patient who developed MRONJ after zolendronate intake for oncological reasons (metastases of breast carcinoma).
3.1. Primary Outcomes
3.1.1. Short-Term Healing
At 1-month post-surgery, 31 out 35 (88.57%) patients showed complete healing. The four not-healed cases were MRONJ stage II: in two cases the picture was stable at last follow-up, while the other two demonstrated a worsening of their conditions. These four patients received zolendronate (in one case alternating to denosumab) for oncological reasons for a mean period of 18.66 ± 4.72 months (range 17–60 months). Two of them had suspended the drug for 10 and 13 months. The mean UCONNS prognostic score was 15.83 ± 7.24 in healed patients, 25 ± 4.08 in not-healed patients (t-test, p = 0.01). Figure 4 describes the short-term healing outcomes depending on UCONNS score.
3.1.2. Long-Term Healing
Twenty-five patients had long-term follow-up (at least 3 months), while the other ten patients, including two patients who did not heal at short-term, were lost prior to further follow-up. In the 25 patients, the mean follow-up was 27.28 ± 15.37 months from the first visit. Twenty-three out 25 (92%) showed complete healing of the surgical site for at least 3 months after surgery (Figure 5). Two patients were not healed at either short-term or long-term follow-up. One of them showed a stable MRONJ lesion in the posterior maxilla, while the other patient with MRONJ at the mandible showed a worsening clinical picture. This patient was referred to maxillofacial surgeons for major surgery. Both not-healed patients had MRONJ stage II and received zoledronate for oncological reasons, respectively for 24 and 17 months. One of the patients was under current zoledronate treatment (in addition to chemotherapy), while the other patient had suspended the drug 13 months before. The mean UCONNS prognostic score was 16.56 ± 7.63 in healed patients, as compared to 22.5 ± 0.7 in not-healed patients (t-test, p = 0.001).
Table 3 reports healing outcomes at long term in patients who received also pentoxifylline and tocopherol therapy.
3.2. Secondary Outcomes
3.2.1. Recurrences
Recurrences were recorded in seven patients out 23 (30.4%) who showed long-term healing: two were stage I, four at stage II, and one was at stage III. The recurrences occurred on average 7.29 ± 3.45 months after surgical intervention. Five out of seven patients who showed recurrences were receiving zoledronate for a mean period of 37.2 ± 24.47 months, while the remaining two patients were under therapy with alendronate for a mean period of 84 ± 16.97 months (Odds Ratio—OR:1.81; 95% CI: 0.27 to 11.86; p = 0.53). Recurrence in the oncological group occurred in five out 15 healed patients, while considering the osteoporotic group in 2 out 8 healed patients (OR 1. 50; 95% CI: 0.21 to 10.30; p = 0.68) (Figure 6).
3.2.2. Adverse Events
No adverse events were reported, except for one case of spontaneous bleeding from the exposed necrotic bone, which occurred soon after the start of pentoxifylline and tocopherol therapy.
4. Discussion
MRONJ is a debilitating condition that more frequently affects females, the elderly, and persons treated for oncological reasons [18,20,28]. Although this complication has important clinical implications for dental practitioners—who need to know the correct management of a patient under anti-resorptive therapy—recent studies highlighted a lack of knowledge among dentists and dental students [29,30,31].
These findings support that, following a combined pharmacological and surgical conservative approach, most patients experience a complete healing. The UCONNS prognostic score was significantly higher in patients with poor healing as compared to those with complete healing in lesions. This conservative approach of MRONJ management was based on previous study outcomes [1,9,21,22] and included systemic antibiotics as well as antiseptic therapy with 0.2% chlorhexidine mouthwash and 1% chlorhexidine gel applied onto exposed necrotic bone [17].
Treatment of MRONJ patients remains challenging, and therapeutic options vary from pharmacological supportive approach with antibiotics and antiseptics to extensive surgical resection of necrotic bone. According to previous studies [14,18,20,32,33], an early surgical approach with appropriate resection margins and primary wound closure can ensure a better surgical outcome (mucosal healing without signs of infection) stage improvement at 6 months, with mucosal and radiographic healing evident at one-year posttreatment. Since pharmacological therapy alone rarely leads to lesion healing even at stage I [16], Khan and colleagues [9], in their systematic review, recommended surgical resection with tension-free primary closure.
In our experience, pharmacological management of MRONJ lesions seems to promote progressive isolation of the bone sequestrum, enabling minimally invasive surgical intervention, with a potentially higher rate of long-term success than major surgical resection. Progressive isolation of necrotic bone throughout the preliminary pharmacologic phase allows removal of necrotic tissue without undue sacrifice of healthy bone.
Consistent with previous research findings on conservative management of MRONJ [16,17,21], a high healing rate was achieved in the present study, although the study sample size was small. Importantly, UCONNS scores were confirmed to play a significant role in influencing treatment outcomes. Indeed, similar to a proposed cut-off value of UCONNS scores ≥ 15 to identify a higher rate of therapeutic failure [34], we found that all non-healed (both stable and worse) patients had a UCONNS score beyond 17.
The rate of recurrence after 3-month healing (30.4%), in the present study, appeared similar to that reported by Mucke and colleagues (28.7%), although they performed only surgical debridement in most of their patients [32]. However, due to methodological heterogeneity, a direct comparison among studies remains still complicated, considering that recurrence may occur after several months and that a too short follow-up period may bias the findings.
The additional use of pentoxifylline and tocopherol in treatment of MRONJ lesions is worth further investigation. In this study, most patients healed without major adverse side effects. Only one patient experienced bleeding at the start of pentoxifylline and tocopherol therapy. The Italian drug agency (AIFA) [35] warned of excessive bleeding among patients receiving anticoagulants, thrombolytic agents, and inhibitors of platelet aggregation who simultaneously are administered pentoxifylline and tocopherol. In our study the patient who developed spontaneous bleeding was not under treatment with any of these drugs.
The main limitation of this retrospective study is the use of medical records not specifically designed for the aim of the study. Thus, collected data might be limited in scope, making identification of potential confounding factors difficult, and making patient inclusion into the study prone to selection bias. Further limitations include varying lengths of follow-up of patients and varying patient compliance with the pharmacological protocol, along with the lack of calibration among the oral surgeons who performed the interventions and a lack of standardization in data collection. The retrospective design also predisposes the study to numerous threats to external validity, which limits interpretation and generalizability of the results (such as single-group threat, i.e., the lack of a comparison and/or control groups, and historical threat, where other events, different from the intervention under investigation, can affect the outcomes) [36].
5. Conclusions
An initial pharmacological phase based on antibiotic and antiseptic agents is useful to gradually isolate bone sequestration in MRONJ patients and facilitate a subsequent surgical phase. This approach is particularly advisable for treatment of stages I and II of MRONJ. UCONNS-related prognostic factors play a relevant role in determining the success of MRONJ therapy.
Author Contributions
Conceptualization, G.L. and E.M.V.; methodology, E.M.V., G.L. and N.L.; validation, G.L. and A.S.; formal analysis, G.L. and E.M.V.; investigation, N.L., A.P. and G.V.; data curation, N.L., G.V. and A.P.; writing—original draft preparation, G.V. and E.M.V.; writing—review and editing, N.L. and G.L.; supervision, G.L. and A.S. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of AO San Paolo (ID protocol approval: ONM-BF-Gene, 2016).
Informed Consent Statement
This study is retrospective study. Opt-out patient consent was obtained.
Data Availability Statement
The data presented in this study are available on request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Flow diagram of enrolled patients.
Figure 2 Clinical case of MRONJ localized in left mandible. (A) Cone beam computed tomography (CBCT) images, sagittal and frontal views, showing isolation of mandibular bone sequestration following antibiotic and topical antiseptic therapy (red arrows indicate the bone sequestrum). (B) Necrotic bone sequestration, resulting from the surgical intervention.
Figure 3 Clinical case of MRONJ localized in the upper maxilla. (A) Cone beam computed tomography (CBCT) images, frontal and sagittal views, showing maxillary bone sequestration (red arrows indicate the bone sequestrum). (B) Intraoral clinical view showing the presence of fistula, which demonstrates the presence of infection. (C) Necrotic bone sequestrum removal, after the opening of the surgical flap (mid-crestal incision on the alveolar crest of the edentulous area). (D) The necrotic bone was completely removed until reaching the healthy bone tissue; bone curettage and osteoplasty were performed until vital bone was clinically observed. (E) Primary closure via periosteal releasing incisions using absorbable suture. (F) Follow-up after 3 months from the surgical intervention showing a complete tissue healing.
Figure 4 Comparison of the short-term healing outcomes depending on University of Connecticut Osteonecrosis Numerical Scale (UCONNS) score.
Figure 5 Comparison of the long-term healing outcomes depending on UCONNS score.
Figure 6 Comparison of long-term healing and recurrence in oncological and osteoporotic group.
antibiotics-10-00195-t001_Table 1 Table 1 Demographic and clinical data concerning patient gender, age, comorbidities, concomitant cancer therapies, stage, and localization of medication-related osteonecrosis of the jaw (MRONJ) (n = 35).
Demographic and Clinical Data Number of Patients (%)
Gender
-Male 11 (31.4%)
-Female 24 (68.6%) *
Age, years Years
Range 51–93
Mean, SD 73.46 ± 9.29
Concomitant cancer therapies
-Steroids 4 (11.4%)
-Chemotherapy 6 (17.1%)
-Steroids and Chemotherapy 4 (11.4%)
-No steroids, No Chemotherapy 21 (60%)
Primary disease requiring anti-resorptive drugs
-Breast cancer 10 (28.6%)
-Prostate cancer 4 (11.4%)
-Multiple myeloma 7 (20%)
-Osteoporosis 14 (40%)
Type of drug associated with MRONJ
Zolendronate 17 (48.5%) *
Alendronate 9 (25.7%)
Denosumab 2 (5.7%)
Alendronate + Denosumab 2 (5.7%)
Alendronate + Risendronate 1(2.9%)
Alendronate + Zolendronate 1(2.9%)
Alendronate + Ibandronate 1(2.9%)
Ibandronate + Clodronate 1 (2.9%)
Zolendronate + Denosumab 1 (2.9%)
Stage of MRONJ
-Stage I 6 (17.1%)
-Stage II 28 (80%)
-Stage III 1 (2.9%) *
MRONJ localization
Maxilla 12 (34.2%)
Mandible 24 (68.5%) * ψ
* χ2 test, significance: p ≤ 0.05. ψ One patient had both mandibular and maxillary lesions.
antibiotics-10-00195-t002_Table 2 Table 2 Clinical data concerning MRONJ-related therapy.
MRONJ-Related Therapy Months
Duration of therapy
-Zoledronate 34.29 ± 33.42
-Alendronate 79.42 ± 63.33
-Denosumab 15 ± 7.94
Suspension of drug
-Zoledronate 8.53 ± 20.21
-Alendronate 13.15 ± 19.58
-Denosumab 0.8 ± 1.1
antibiotics-10-00195-t003_Table 3 Table 3 Clinical outcomes of patients who received pentoxifylline and tocopherol therapy for management of MRONJ.
Age (Years) Cause of Anti-Resorptive Treatment Gender Type of MRONJ-Related Drug UCONNS Score Stage of MRONJ Site of MRONJ Outcomes
68 Cancer Female Alendronate 12 Stage II Mandible Healed
65 Cancer Female Zoledronate 23 Stage II Mandible Worsened
53 Cancer Female Zoledronate 31 Stage II Mandible Stable
51 Cancer Female Zoledronate-Denosumab 24 Stage II Maxilla Worsened
93 Osteoporosis Female Alendronate-Denosumab 13 Stage II Maxilla/Mandible Healed
85 Cancer Female Zoledronate 26 Stage II Maxilla Healed
65 Cancer Male Denosumab 22 Stage II Mandible Healed
90 Osteoporosis Female Alendronate 8 Stage II Maxilla Healed
77 Cancer Male Zoledronate 21 Stage II Mandible Healed
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ALENDRONATE (24 MONTHS) | DrugDosageText | CC BY | 33671429 | 19,769,348 | 2021-02-17 |
What was the outcome of reaction 'Surgery'? | Conservative Management of Medication-Related Osteonecrosis of the Jaws (MRONJ): A Retrospective Cohort Study.
BACKGROUND
Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of bisphosphonates and anti-resorptive drugs prescribed for treatment of severe osteoporosis, Paget's disease, and bone malignancies. The aim of this study was to evaluate the clinical outcome of a combined pharmacological and surgical management strategy on patients affected by MRONJ.
METHODS
Medical records of patients with MRONJ were retrospectively examined to collect clinical history data. Conservative management included an initial pharmacological phase with antibiotics and antiseptic agents, followed by surgical intervention to remove bone sequestrum. Primary outcomes were healing from MRONJ at short term (1 month after surgery) and at longer term (3 months after surgery). Secondary outcome was assessment of recurrences at longer-term follow-up.
RESULTS
Thirty-five patients were included in the study with mean follow-up of 23.86 ± 18.14 months. Seven cases showed spontaneous exfoliation of necrotic bone during pharmacological therapy, which in one case did not require any further intervention. At 1-month posttreatment, 31 out of 35 (88.5%) patients showed complete healing. The 25 patients who were followed for at least 3 months revealed a healing rate of 92% (23/25). Recurrences occurred in 7 patients out 23 who showed the long-term healing, after a mean period of 7.29 ± 3.45 months. The prognostic score (University of Connecticut Osteonecrosis Numerical Scale-UCONNS) was significantly higher (p = 0.01) in patients with poor healing as compared to complete healing, both at 1 and 3 months posttreatment.
CONCLUSIONS
A MRONJ treatment approach based on a combined pharmacological and surgical treatment strategy showed a high rate of healing and few recurrences.
1. Introduction
As defined in 2014 by the American Association of Oral and Maxillofacial Surgeons (AAOMS), medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of bisphosphonates and of certain anti-resorptive drugs, such as denosumab [1], commonly prescribed for controlling severe osteoporosis, Paget’s disease, and bone malignancies, including multiple myeloma and bone metastases [1]. Bisphosphonates (BPs) are analogues of inorganic pyrophosphate, inhibiting the pyrophosphate-dependent enzymes mediating bone resorption [2]. Denosumab is a human monoclonal immunoglobulin G2 subclass (IgG2) that mimics the function of the endogenous molecule osteoprotegerin (OPG), reducing bone metabolism [3]. Even if the potential of BPs and denosumab to increase the survival in cancer patients remains uncertain, they significantly improve the quality of life, reducing bone pain in cases of advanced bone metastases [4].
MRONJ pathogenesis is still largely unknown. A multi-factorial mechanism has been advocated, involving inhibition of angiogenesis and remodeling in bone tissue, presence of continuous micro-trauma within the oral cavity during eating and speaking, as well as a potential role and impact from oral mucosal inflammation or odontogenic infection [5,6].
A recognized risk factor for MRONJ is high concentration and long duration of BP intake [7]. The frequency of MRONJ in cancer patients has been estimated, ranging from 1% to 15%, while the frequency in patients with osteoporosis, receiving much lower BP doses, is estimated around 0.001% to 0.01% [8,9]. Antiangiogenic agents, tyrosine kinase inhibitors, and monoclonal antibody-targeting Vascular-Endothelial Growth Factor (VEGF)—such as sunitimib, sorafefenib, bevacizumab—worsen the risk of MRONJ from 5- to 10-fold [1,10]. Since MRONJ negatively impacts patient quality of life [11], preventive dental treatment is strongly recommended [12].
Despite no international consensus for treating MRONJ, a decisional tree to manage these patients requires consideration of the staging of MRONJ, patient age, gender, and systemic health [9]. The primary objective of treatment is to control symptoms, mainly pain, and to avoid progression of MRONJ to a more advanced stage [13]. Recent studies suggest a need for early surgical management to ensure complete removal of the necrotic bone following implementation of a first-line conservative nonsurgical approach with antibiotics, antimicrobials, and analgesics [13,14,15,16,17]. Surgery, in particular, is recommended in the presence of well-defined bone sequestra; in these cases, sequestrectomy or surgical debridement is needed. In patients with advanced stages who show a progression of the disease, or in cases of persistent pain and infection despite the medical therapy, an extensive resection is required [1,18,19]. Medical therapy itself appears to control pain and infection in about 50% of patients. A risk of sepsis, mainly in immunocompromised cancer patients, further justifies surgical intervention [19]. To date, MRONJ surgical therapy has been associated with variable percentages of success due to high heterogeneity among published studies [18,20,21].
The aim of this study was to retrospectively assess the success and recurrence rates in a cohort of MRONJ patients treated with a first pharmacological phase, intended for isolating gradually necrotic bone tissue and promoting sequestration, followed by a surgical intervention limiting the need for extensive resections.
2. Materials and Methods
2.1. Patients
2.1.1. Study Design and Patient Population
This cohort study retrospectively analyzed clinical records of MRONJ patients referred to the Oral Medicine Unit (ASST Santi Paolo e Carlo) at University of Milan, from October 2008 to December 2017. MRONJ staging of affected patients was defined according to 2014 AAOMS criteria [1].
2.1.2. Eligibility Criteria
The inclusion criteria included patients with MRONJ diagnosis at stage I–III, according to AAOMS criteria [1,21]. All patients were treated first with a pharmacological phase and then a surgical phase for bone sequestration removal [1,13,14,15,16,17]. The exclusion criteria were [1]: history of radiation therapy to the jaws or obvious metastatic disease to the jaws, no history of pharmacological therapy for MRONJ, and no history of surgical removal or spontaneous exfoliation of bone sequestra.
2.1.3. Treatment Intervention
Each patient received two phases of management, i.e., a pharmacological phase and a surgical phase. Based on previous literature [1,13,14,15,16,17], the protocol first used a medical management approach with antibiotics and local measures and followed the patients until there was evidence of bone sequester formation. At that point, surgical treatment of the MRONJ lesion site was performed with the goal of removing the sequestered bone and debridement of the site. In recurrent cases, the patients were referred to maxillofacial surgeons for major surgical procedures, i.e., bone resection.
Based on previous studies [1,9,21,22], systemic antibiotics were prescribed to all study patients as follows: amoxicillin 3 g/day or clindamycin 1800 mg/day in cases of allergy to the penicillin; for the cases scarcely responsive to single-antibiotic therapy, metronidazole 500 mg/day for a maximum 14 days. Topical antiseptic therapy with 0.2% chlorhexidine mouthwash and 1% chlorhexidine gel, applied onto exposed necrotic bone, was also prescribed [17].
Surgical intervention (sequestrectomy) was performed when sequestered bone was clinically or radiographically evident and not spontaneously exfoliated, following a MRONJ protocol previously recommended [23]. Briefly, one week before surgical intervention, each patient received the dental scaling, topical antiseptic therapy (0.2% chlorhexidine mouthwash, twice/day), and the prescription of antibiotic therapy started three days before the surgery (amoxicillin 3 g/day, or clindamycin 1800 mg/day in case of allergy to penicillin) [23]. On the day of surgical intervention, under local anesthesia, necrotic bone was removed via full-thickness mucoperiosteal flap, with minimal trauma to the cortical plates. Teeth involved in the necrotic area were extracted and a meticulous bone curettage and osteoplasty were performed until clear bleeding and white vital bone were clinically evident. The flap was closed with an absorbable suture via periosteal releasing incisions to achieve primary closure and in order to maximize the vascular supply to the area as well as to reduce risk of infection at the surgical site. Post-surgery, patients continued for two weeks the systemic antibiotic therapy and antiseptic mouthwash and also applied 1% chlorhexidine gel onto the surgical wound twice/day for at least 14 days. On the basis of the promising results obtained in previous studies [24,25,26], and under approval of the patient’s oncologist, pentoxifylline and tocopherol were also prescribed per os (pentoxifylline 800 mg/day + tocopherol 800 U.I./day), before and/or after surgical intervention, according to clinical case.
2.2. Data Collection
Clinical and demographic data collected for each patient included, age, gender, systemic conditions, MRONJ stage [1], bisphosphonate, anti-resorptive, or anti-angiogenetic therapy (dosage, suspension, and duration), formation of bone sequestra, area of exposed bone (localization and size), date of surgical intervention(s), number of recurrences, and length of follow-up. The duration of therapy was determined as the period from the start of treatment to the first visit to our clinical unit. The prognostic score (University of Connecticut Osteonecrosis Numerical Scale—UCONNS) described by Landesberg was applied to find possible correlation between outcomes and patient systemic conditions [27]. UCONNS scores assess the individual prognosis based on known risk factors for MRONJ management failure, including systemic health conditions, comorbidities, type, and duration of bisphosphonate therapy and type of intervention performed. UCONNS scores were categorized as follow: 0–8, 9–16, 17–24, 25–32.
2.3. Outcomes
2.3.1. Primary Outcomes: Clinical Healing
The following criteria for clinical healing were used (adapted from [28]):Short-term healing—A patient was defined as “healed at short-term”, if presenting, for at least 1 month after sequestrectomy or spontaneous exfoliation of necrotic bone, the following clinical picture: absence of exposed necrotic bone or bone that can be probed through a fistula; absence of purulent drainage; absence of edema and stimulated pain; complete mucosal coverage of the surgical site.
Long-term healing—A patient was defined as “healed at long-term”, if presenting the same clinical picture described above but lasting for at least 3 months after sequestrectomy or spontaneous exfoliation of bone sequestration.
Stable MRONJ clinical picture—A patient was “stable” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with the same stage seen during the first visit.
Worsened MRONJ clinical picture—A patient was “worsened” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with a worse stage than found at first diagnosis.
Improved MRONJ clinical picture—A patient was “improved” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with a better stage than the one of the first diagnosis.
2.3.2. Secondary Outcomes: Rate of MRONJ Recurrence
Recurrence
Recurrence was defined as the appearance of exposed necrotic bone or bone that could be probed through a fistula, in association or not with radiographic evidence of architectural bone changes persisting for more than 8 weeks in an area that had already demonstrated a long-term healing.
Adverse Effects
Any adverse events due to pharmacological and/or surgical phases were recorded when specified in the medical record.
2.4. Statistical Analysis
Means and standard deviations were calculated for continuous variables; Kolmogorov–Smirnov test of normality was applied, and data were normally distributed. A t-test was used to compare means between two unpaired samples. For categorical variables, extracted data were expressed as percentages, and statistical analyses to identify significant differences were performed by applying the χ2 test using the online Graphpad statistical software (GraphPad Software®, San Diego, CA, USA). Statistical significance was set at p ≤ 0.05. Odds ratios were also calculated using the online MedCalc Software Ltd statistical software (MedCalc Software Ltd., Ostend, Belgium).
2.5. Ethical Approval
The study was performed under ethical approval obtained from the Ethic Committee of the AO San Paolo (ID study approval: ONM-BF-Gene, 2016). Opt-out patient consent was obtained.
2.6. STROBE Statement
The Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement was used to prepare this report.
3. Results
From an initial cohort of 45 patients with MRONJ, 35 subjects were included in the study. Ten patients were excluded for the following reasons: positive anamnesis for head and neck radiotherapy (n = 2), or insufficient clinical data (n = 8). Figure 1 provides a flow-chart of enrolled study patients, while patient demographic and clinical data are summarized in Table 1.
Most of patients were women (χ2; p = 0.02); the mean age of study participants at the first examination was 73.46 ± 9.29 years (range 51–93 years) (Table 1). Six patients out thirty-five were undergoing anticancer chemotherapy at the moment of surgical intervention. Eight patients were receiving intravenous steroid treatment, which in four cases was associated with the chemotherapeutic regimen (Table 1). Six patients were also affected by diabetes.
Most patients were treated with zoledronate and showed stage II MRONJ lesions (Table 1).
The mean follow-up of patients, from the first visit up to the last one available, was 23.86 ± 18.14 months (range: 1–74 months). The mean therapy with zoledronate lasted 34.29 ± 33.42 months; in some cases, the drug was suspended for a mean period of 8.53 ± 20.21 months. The mean duration of alendronate therapy was longer (79.42 ± 63.33 months), with a mean suspension period, when occurring, of 13.15 ± 19.58 months. The mean duration of the therapy with denosumab was shorter, lasting 15 ± 7.94 months, with a mean suspension time of 0.8 ± 1.1 months (Table 2).
The pharmacological phase involved the use of topical chlorhexidine and systemic amoxicillin, with 11 patients also receiving metronidazole. In nine patients (25.71%), the supportive pharmacological therapy for MRONJ included also pentoxifylline and tocopherol (mean period of administration 3.81 ± 2.46 months).
Seven cases showed spontaneous exfoliation of necrotic bone. In four cases, the exfoliation occurred during the pharmacological phase: in one case, the sequestrum was completely exfoliated not requiring any further intervention, while in three patients the sequestra were partially exfoliated, requiring the further surgical intervention at the same site. In the other three patients, a spontaneous exfoliation of an additional bone sequestrum followed sequestrectomy.
Fifty-seven interventions of sequestrectomy were performed. Eighteen patients received a single surgical intervention, while four patients underwent two interventions in two different sites affected by MRONJ. In five subjects, the interventions were more than two; one patient required five interventions at the same site.
Figure 2 describes a clinical case where antibiotic administration gradually resulted in the isolation of bone sequestrum from the surrounding healthy bone.
Figure 3A–F describes the surgical intervention for bone sequestrum removal in a patient who developed MRONJ after zolendronate intake for oncological reasons (metastases of breast carcinoma).
3.1. Primary Outcomes
3.1.1. Short-Term Healing
At 1-month post-surgery, 31 out 35 (88.57%) patients showed complete healing. The four not-healed cases were MRONJ stage II: in two cases the picture was stable at last follow-up, while the other two demonstrated a worsening of their conditions. These four patients received zolendronate (in one case alternating to denosumab) for oncological reasons for a mean period of 18.66 ± 4.72 months (range 17–60 months). Two of them had suspended the drug for 10 and 13 months. The mean UCONNS prognostic score was 15.83 ± 7.24 in healed patients, 25 ± 4.08 in not-healed patients (t-test, p = 0.01). Figure 4 describes the short-term healing outcomes depending on UCONNS score.
3.1.2. Long-Term Healing
Twenty-five patients had long-term follow-up (at least 3 months), while the other ten patients, including two patients who did not heal at short-term, were lost prior to further follow-up. In the 25 patients, the mean follow-up was 27.28 ± 15.37 months from the first visit. Twenty-three out 25 (92%) showed complete healing of the surgical site for at least 3 months after surgery (Figure 5). Two patients were not healed at either short-term or long-term follow-up. One of them showed a stable MRONJ lesion in the posterior maxilla, while the other patient with MRONJ at the mandible showed a worsening clinical picture. This patient was referred to maxillofacial surgeons for major surgery. Both not-healed patients had MRONJ stage II and received zoledronate for oncological reasons, respectively for 24 and 17 months. One of the patients was under current zoledronate treatment (in addition to chemotherapy), while the other patient had suspended the drug 13 months before. The mean UCONNS prognostic score was 16.56 ± 7.63 in healed patients, as compared to 22.5 ± 0.7 in not-healed patients (t-test, p = 0.001).
Table 3 reports healing outcomes at long term in patients who received also pentoxifylline and tocopherol therapy.
3.2. Secondary Outcomes
3.2.1. Recurrences
Recurrences were recorded in seven patients out 23 (30.4%) who showed long-term healing: two were stage I, four at stage II, and one was at stage III. The recurrences occurred on average 7.29 ± 3.45 months after surgical intervention. Five out of seven patients who showed recurrences were receiving zoledronate for a mean period of 37.2 ± 24.47 months, while the remaining two patients were under therapy with alendronate for a mean period of 84 ± 16.97 months (Odds Ratio—OR:1.81; 95% CI: 0.27 to 11.86; p = 0.53). Recurrence in the oncological group occurred in five out 15 healed patients, while considering the osteoporotic group in 2 out 8 healed patients (OR 1. 50; 95% CI: 0.21 to 10.30; p = 0.68) (Figure 6).
3.2.2. Adverse Events
No adverse events were reported, except for one case of spontaneous bleeding from the exposed necrotic bone, which occurred soon after the start of pentoxifylline and tocopherol therapy.
4. Discussion
MRONJ is a debilitating condition that more frequently affects females, the elderly, and persons treated for oncological reasons [18,20,28]. Although this complication has important clinical implications for dental practitioners—who need to know the correct management of a patient under anti-resorptive therapy—recent studies highlighted a lack of knowledge among dentists and dental students [29,30,31].
These findings support that, following a combined pharmacological and surgical conservative approach, most patients experience a complete healing. The UCONNS prognostic score was significantly higher in patients with poor healing as compared to those with complete healing in lesions. This conservative approach of MRONJ management was based on previous study outcomes [1,9,21,22] and included systemic antibiotics as well as antiseptic therapy with 0.2% chlorhexidine mouthwash and 1% chlorhexidine gel applied onto exposed necrotic bone [17].
Treatment of MRONJ patients remains challenging, and therapeutic options vary from pharmacological supportive approach with antibiotics and antiseptics to extensive surgical resection of necrotic bone. According to previous studies [14,18,20,32,33], an early surgical approach with appropriate resection margins and primary wound closure can ensure a better surgical outcome (mucosal healing without signs of infection) stage improvement at 6 months, with mucosal and radiographic healing evident at one-year posttreatment. Since pharmacological therapy alone rarely leads to lesion healing even at stage I [16], Khan and colleagues [9], in their systematic review, recommended surgical resection with tension-free primary closure.
In our experience, pharmacological management of MRONJ lesions seems to promote progressive isolation of the bone sequestrum, enabling minimally invasive surgical intervention, with a potentially higher rate of long-term success than major surgical resection. Progressive isolation of necrotic bone throughout the preliminary pharmacologic phase allows removal of necrotic tissue without undue sacrifice of healthy bone.
Consistent with previous research findings on conservative management of MRONJ [16,17,21], a high healing rate was achieved in the present study, although the study sample size was small. Importantly, UCONNS scores were confirmed to play a significant role in influencing treatment outcomes. Indeed, similar to a proposed cut-off value of UCONNS scores ≥ 15 to identify a higher rate of therapeutic failure [34], we found that all non-healed (both stable and worse) patients had a UCONNS score beyond 17.
The rate of recurrence after 3-month healing (30.4%), in the present study, appeared similar to that reported by Mucke and colleagues (28.7%), although they performed only surgical debridement in most of their patients [32]. However, due to methodological heterogeneity, a direct comparison among studies remains still complicated, considering that recurrence may occur after several months and that a too short follow-up period may bias the findings.
The additional use of pentoxifylline and tocopherol in treatment of MRONJ lesions is worth further investigation. In this study, most patients healed without major adverse side effects. Only one patient experienced bleeding at the start of pentoxifylline and tocopherol therapy. The Italian drug agency (AIFA) [35] warned of excessive bleeding among patients receiving anticoagulants, thrombolytic agents, and inhibitors of platelet aggregation who simultaneously are administered pentoxifylline and tocopherol. In our study the patient who developed spontaneous bleeding was not under treatment with any of these drugs.
The main limitation of this retrospective study is the use of medical records not specifically designed for the aim of the study. Thus, collected data might be limited in scope, making identification of potential confounding factors difficult, and making patient inclusion into the study prone to selection bias. Further limitations include varying lengths of follow-up of patients and varying patient compliance with the pharmacological protocol, along with the lack of calibration among the oral surgeons who performed the interventions and a lack of standardization in data collection. The retrospective design also predisposes the study to numerous threats to external validity, which limits interpretation and generalizability of the results (such as single-group threat, i.e., the lack of a comparison and/or control groups, and historical threat, where other events, different from the intervention under investigation, can affect the outcomes) [36].
5. Conclusions
An initial pharmacological phase based on antibiotic and antiseptic agents is useful to gradually isolate bone sequestration in MRONJ patients and facilitate a subsequent surgical phase. This approach is particularly advisable for treatment of stages I and II of MRONJ. UCONNS-related prognostic factors play a relevant role in determining the success of MRONJ therapy.
Author Contributions
Conceptualization, G.L. and E.M.V.; methodology, E.M.V., G.L. and N.L.; validation, G.L. and A.S.; formal analysis, G.L. and E.M.V.; investigation, N.L., A.P. and G.V.; data curation, N.L., G.V. and A.P.; writing—original draft preparation, G.V. and E.M.V.; writing—review and editing, N.L. and G.L.; supervision, G.L. and A.S. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of AO San Paolo (ID protocol approval: ONM-BF-Gene, 2016).
Informed Consent Statement
This study is retrospective study. Opt-out patient consent was obtained.
Data Availability Statement
The data presented in this study are available on request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Flow diagram of enrolled patients.
Figure 2 Clinical case of MRONJ localized in left mandible. (A) Cone beam computed tomography (CBCT) images, sagittal and frontal views, showing isolation of mandibular bone sequestration following antibiotic and topical antiseptic therapy (red arrows indicate the bone sequestrum). (B) Necrotic bone sequestration, resulting from the surgical intervention.
Figure 3 Clinical case of MRONJ localized in the upper maxilla. (A) Cone beam computed tomography (CBCT) images, frontal and sagittal views, showing maxillary bone sequestration (red arrows indicate the bone sequestrum). (B) Intraoral clinical view showing the presence of fistula, which demonstrates the presence of infection. (C) Necrotic bone sequestrum removal, after the opening of the surgical flap (mid-crestal incision on the alveolar crest of the edentulous area). (D) The necrotic bone was completely removed until reaching the healthy bone tissue; bone curettage and osteoplasty were performed until vital bone was clinically observed. (E) Primary closure via periosteal releasing incisions using absorbable suture. (F) Follow-up after 3 months from the surgical intervention showing a complete tissue healing.
Figure 4 Comparison of the short-term healing outcomes depending on University of Connecticut Osteonecrosis Numerical Scale (UCONNS) score.
Figure 5 Comparison of the long-term healing outcomes depending on UCONNS score.
Figure 6 Comparison of long-term healing and recurrence in oncological and osteoporotic group.
antibiotics-10-00195-t001_Table 1 Table 1 Demographic and clinical data concerning patient gender, age, comorbidities, concomitant cancer therapies, stage, and localization of medication-related osteonecrosis of the jaw (MRONJ) (n = 35).
Demographic and Clinical Data Number of Patients (%)
Gender
-Male 11 (31.4%)
-Female 24 (68.6%) *
Age, years Years
Range 51–93
Mean, SD 73.46 ± 9.29
Concomitant cancer therapies
-Steroids 4 (11.4%)
-Chemotherapy 6 (17.1%)
-Steroids and Chemotherapy 4 (11.4%)
-No steroids, No Chemotherapy 21 (60%)
Primary disease requiring anti-resorptive drugs
-Breast cancer 10 (28.6%)
-Prostate cancer 4 (11.4%)
-Multiple myeloma 7 (20%)
-Osteoporosis 14 (40%)
Type of drug associated with MRONJ
Zolendronate 17 (48.5%) *
Alendronate 9 (25.7%)
Denosumab 2 (5.7%)
Alendronate + Denosumab 2 (5.7%)
Alendronate + Risendronate 1(2.9%)
Alendronate + Zolendronate 1(2.9%)
Alendronate + Ibandronate 1(2.9%)
Ibandronate + Clodronate 1 (2.9%)
Zolendronate + Denosumab 1 (2.9%)
Stage of MRONJ
-Stage I 6 (17.1%)
-Stage II 28 (80%)
-Stage III 1 (2.9%) *
MRONJ localization
Maxilla 12 (34.2%)
Mandible 24 (68.5%) * ψ
* χ2 test, significance: p ≤ 0.05. ψ One patient had both mandibular and maxillary lesions.
antibiotics-10-00195-t002_Table 2 Table 2 Clinical data concerning MRONJ-related therapy.
MRONJ-Related Therapy Months
Duration of therapy
-Zoledronate 34.29 ± 33.42
-Alendronate 79.42 ± 63.33
-Denosumab 15 ± 7.94
Suspension of drug
-Zoledronate 8.53 ± 20.21
-Alendronate 13.15 ± 19.58
-Denosumab 0.8 ± 1.1
antibiotics-10-00195-t003_Table 3 Table 3 Clinical outcomes of patients who received pentoxifylline and tocopherol therapy for management of MRONJ.
Age (Years) Cause of Anti-Resorptive Treatment Gender Type of MRONJ-Related Drug UCONNS Score Stage of MRONJ Site of MRONJ Outcomes
68 Cancer Female Alendronate 12 Stage II Mandible Healed
65 Cancer Female Zoledronate 23 Stage II Mandible Worsened
53 Cancer Female Zoledronate 31 Stage II Mandible Stable
51 Cancer Female Zoledronate-Denosumab 24 Stage II Maxilla Worsened
93 Osteoporosis Female Alendronate-Denosumab 13 Stage II Maxilla/Mandible Healed
85 Cancer Female Zoledronate 26 Stage II Maxilla Healed
65 Cancer Male Denosumab 22 Stage II Mandible Healed
90 Osteoporosis Female Alendronate 8 Stage II Maxilla Healed
77 Cancer Male Zoledronate 21 Stage II Mandible Healed
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory failure'. | Pearls and Pitfalls of Introducing Ketogenic Diet in Adult Status Epilepticus: A Practical Guide for the Intensivist.
Background: Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of a ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and effective. Methods: We describe our experience, including the challenges of achieving and maintaining ketosis, in an adult with new onset refractory status epilepticus (NORSE). Case Vignette: A previously healthy 29-year-old woman was admitted with cryptogenic NORSE following a febrile illness; course was complicated by prolonged super-refractory SE. A comprehensive work-up was notable only for mild cerebral spinal fluid (CSF) pleocytosis, elevated nonspecific serum inflammatory markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI). Repeat CSF testing was normal and serial MRIs demonstrated resolution of edema and diffusion restriction with progressive hippocampal and diffuse atrophy. She required prolonged therapeutic coma with high anesthetic infusion rates, 16 antiseizure drug (ASD) trials, empiric immunosuppression and partial bilateral oophorectomy. Enteral ketogenic formula was started on hospital day 28. However, sustained beta-hydroxybutyrate levels >2 mmol/L were only achieved 37 days later following a comprehensive adjustment of the care plan. KD was challenging to maintain in the intensive care unit (ICU) and was discontinued due to poor nutritional state and pressure ulcers. KD was restarted again in a non-ICU unit facilitating ASD tapering without re-emergence of SE. Discussion: There are inconspicuous carbohydrates in commonly administered medications for SE including antibiotics, electrolyte repletion formulations, different preparations of the same drug (i.e., parenteral, tablet, or suspension) and even solutions used for oral care-all challenging the use of KD in the hospitalized patient. Tailoring comprehensive care and awareness of possible complications of KD are important for the successful implementation and maintenance of ketosis.
1. Introduction
Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and potentially effective [1,2,3,4,5]. Most often used in childhood epilepsies, KD has emerged as a potential adjunctive treatment for pediatric SE [6,7]. We describe our experience with an adult with new onset refractory status epilepticus (NORSE) focusing on the unexpected challenge of achieving and maintaining ketosis. Practical advice, and a comprehensive review of factors potentially jeopardizing ketosis commonly encountered in the critical care setting and alternatives are provided.
2. Presentation
A previously healthy 29-year-old woman was admitted to another institution with new onset refractory status epilepticus (NORSE) following a febrile illness with a course complicated by prolonged super-refractory SE. Three days prior to presentation she developed fever, headache, emesis and fatigue in the setting of being in contact with her child with an upper respiratory tract infection. On the morning of admission, her friend attempted to awaken her for work and found her unresponsive and convulsing. In the emergency department, she was lethargic and mumbling incoherently. During her initial evaluation she had a witnessed 45-s bilateral tonic-clonic seizure that was aborted with 2 mg lorazepam intravenously. Head computed tomography was unremarkable and initial cerebrospinal fluid (CSF) analysis showed a mononuclear pleocytosis (2 RBC, 41 nucleated cells (57% mononuclear cells), glucose 93, protein 54)). A one-hour electroencephalogram (EEG) showed diffuse delta activity admixed with sleep spindles and K complexes without epileptiform discharges. She was monitored in the step-down unit and treated with levetiracetam and acyclovir. On hospital day two, she was somnolent but arousable to voice; she was able to follow simple midline commands, state her name and the current president, but was disoriented to time. She was noted to have twitching of her face, but no EEG was done at that time. By hospital day three, she began experiencing brief convulsive seizures which were aborted with intravenous lorazepam and always associated with recovery of consciousness. At that point, phenytoin (1 g loading dose, maintenance at 100 mg q8h) was added to her antiseizure drug (ASD) regimen. On hospital day four, she had multiple convulsive seizures without return to baseline, complicated by acute hypoxic respiratory failure requiring intubation. She was transferred to the intensive care unit (ICU) where she was started on propofol, and valproic acid (20 mg/kg loading dose, maintenance at 750 mg Q8H) was added. Routine EEG captured multiple discrete right frontal and centrotemporal onset seizures correlating with episodes of face twitching. She was started on pentobarbital infusion (5 mg/kg bolus, maintenance at 1 mg/kg per hour) and transferred to our center for continuous EEG monitoring.
3. Question: How Is Prolonged Seizure Activity Classified and What Are Potential Etiologies to Be Considered?
According to the most recent classification set by The International League Against Epilepsy, SE is a “condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures” [8]. While operational SE definitions based on time-domains vary according to seizure type, it is generally accepted that convulsive seizure activity lasting either greater than 5 min continuously, or two or more seizures during which the individual does not recover to baseline between seizures, represents SE [8]. Inhibitory gamma-aminobutyric acid (GABA) neurons located in the pars reticulata of the substantia nigra are key in seizure termination [9]. During status epilepticus, marked alteration of GABA metabolism occurs in this region and results in disinhibition of excitatory pathways: GABA synthesis slows down [10]. GABA turnover time increases up to three-fold, [10] and GABA receptors (originally located in the surface of the cell membrane) migrate to the intracellular space within minutes of ongoing seizure activity [11,12,13]. Prompt initiation of abortive therapies is key, as the internalization of GABA receptors contributes to refractoriness to treatment.
Emergent administration of parenteral benzodiazepine (e.g., up to 0.1 mg/kg of lorazepam) is considered the first-line therapy for SE [14]. If a patient fails to respond to a benzodiazepine and a second appropriately selected and dosed ASD at adequate doses, they are in refractory status epilepticus (RSE). It has been reported that one in five RSE patients go on to develop super-refractory status epilepticus (SRSE), defined as (1) ongoing seizures lasting 24 h or more after onset of anesthetic therapy (i.e., propofol) or (2) recurrence of SE upon reduction or withdrawal of therapeutic anesthetic coma [15]. The clinical presentation of RSE in patients without overt acute or remote brain injury, prior epilepsy, or acute toxic/metabolic explanation is consistent with New Onset Refractory Status Epilepticus—NORSE [16]. Febrile Infection-Related Epilepsy Syndrome (FIRES) is a subset of NORSE, in which a febrile infectious illness precedes SE onset by 1–14 days [14,15,16]. Thus, our patient qualified as having the syndrome of FIRES as well as NORSE. Further, clinical criteria for unequivocal electroencephalographic status epilepticus in patients without known epileptic encephalopathy has been established in the Salzburg consensus: (1) repeating epileptiform discharges occurring >2.5 Hz, or (2) repeating epileptiform discharges occurring ≤2.5 Hz or rhythmic delta/theta activity >0.5 Hz plus (a) electroclinical response (improvement) following intravenous ASD challenge, (b) subtle clinical correlate associated with pattern, or (c) typical temporal and spatial evolution of pattern [17].
Determining the underlying etiology of SE may seem a daunting task. However, its importance in achieving seizure cessation cannot be underestimated. Outcome following SE is dependent on the etiology of seizures. Further, appropriately recognizing the electroclinical classification of seizures (i.e., identifying the seizure semiology and its electrographic signature) may not only help selection of therapy but also identify potential etiologies [8]. Among NORSE patients, an etiology is found in up to 50% of cases [16]. Of those with an identifiable cause, the majority (37%) had an autoimmune cause (both nonparaneoplatic and paraneoplastic), while 8% had a probable infectious cause [16]. Thus, if an autoimmune etiology is diagnosed or clinically suspected, immune modulating therapies such as high-dose corticosteroids, intravenous immunoglobulin (IVIg) or plasma exchange therapy, followed by monoclonal antibodies and/or interleukin inhibitors, should be considered early in the course.
Our patient underwent a comprehensive work-up to determine the etiology of NORSE, as summarized on Table 1, which was notable only for mild CSF pleocytosis, elevated nonspecific inflammatory serum markers and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI).
4. Question: What Are the Initial Steps in the Therapeutic Algorithm for Status Epilepticus?
Benzodiazepines are the first-line treatment for SE [14,19] with slower-acting, less sedating parenteral ASDs being the second line (e.g., phenytoin, fosphenytoin, valproate and levetiracetam; and possibly lacosamide and phenobarbital). The Established Status Epilepticus Treatment Trial (ESETT) found no difference in efficacy between fosphenytoin (20 mgPE/kg), valproate (40 mg/kg) and levetiracetam (60 mg/kg) in children, adults and older adults; these ASDs were able to abort SE within an hour in nearly 50% of patients [20]. Once the second-line, or a combination of medications, fails to result in seizure cessation, continuous intravenous infusions of anesthetics (i.e., midazolam, pentobarbital, propofol, ketamine) are often recommended [14,19].
In patients with SE, anesthetic use is associated with longer hospital stay, but not in-hospital or 90-day mortality [21]. Amongst NORSE patients who receive anesthetics, the mortality is high. However, the use of anesthetics is not associated with poor outcome [16]. In 61 patients with RSE, those who underwent deep sedation (defined as either EEG showing burst suppression or isoelectric activity) had both poorer long-term prognosis and increased mortality [22]. Burst suppression on EEG is defined as intermittent alternating periods of low amplitudes (<10 uV for burst suppression; 10–20 uV for burst attenuation) interrupting a background, which may consist of waves of varying frequencies. Earlier attainment of burst suppression may allow for a more rapid anesthetic wean [23], and it is important to frequently monitor the EEG and titrate anesthetic dose as appropriate. The goal of anesthetic use in RSE is the resolution of epileptiform activity in order to avoid physiologic effects while the underlying cause is identified and treated [24,25].
In our case, 16 antiseizure drug trials in various combinations and high anesthetic infusion rates were attempted. RSE persisted despite 160 mg/h (2.5 mg/kg/h) of midazolam prompting the initiation of ketamine. Despite improved seizure burden following ketamine bolus (1.5 mg/kg), reemergence of SE occurred despite up-titration of ketamine to our maximum infusion rate (7.5 mg/kg/h). Her EEG responded to propofol and pentobarbital with long periods of suppression, although her background remained with abundant generalized periodic discharges (GPD) at 2.5–3 Hz, qualifying as ongoing electrographic SE. [17,26] Burst suppression was eventually achieved with pentobarbital at 3 mg/kg/h and propofol at 40 mcg/kg/min. However, due to re-emergence of 2 Hz GPDs along with breakthrough seizures on attempted wean, she remained in a medically induced coma for over three months.
5. Question: What Are Potential Rescue Therapeutic Approaches to the Management of Super-Refractory Status Epilepticus?
Refractory and super-refractory SE and their complications are associated with significant morbidity including death, neuronal damage and systemic complications like cardiomyopathy, ischemic bowel, pulmonary edema and renal failure [27]. This highlights the necessity for a prompt and aggressive treatment approach. In the setting of treatment failure, alternative treatment options include inhaled anesthetics, magnesium infusion, pyridoxine, hypothermia, electrical and magnetic stimulation, additional immunotherapy, enteral ASDs and the KD [28].
Given a high suspicion for an autoimmune process, our patient was treated with intravenous methylprednisolone (1 g daily for 5 days), IVIg, plasma exchange and cyclophosphamide. Serial MRIs demonstrated resolution of edema and diffusion restriction with gradually progressive atrophy, predominantly in the hippocampi, and repeat CSF analysis was normal. She underwent empiric bilateral partial oophorectomy for an echogenic focus in her left ovary and concern for possible occult microteratoma, possibly secondary to N-methyl-D-Aspartate (NMDA) encephalitis (NMDA CSF < 1:1 and serum < 1:10) [29].
6. Ketogenic Diet
Ketosis is commonly defined as sustained beta-hydroxybutyrate levels > 2 mmol/L [30] or a urinary acetoacetate level of >40 mg/dL [31]. There is evidence supporting the use of KD in children with autoimmune epilepsies, symptomatic epilepsy syndromes, pediatric refractory and super-refractory SE [6,32]. In a study of 10 children (age six months—16 years old) with refractory focal SE, initiation of a KD resulted in lower seizure burden (50% reduction in seizures for 70% of the cohort) and resolution of seizures in 20% [6]. In the minority of patients with less than 50% seizure reduction (n = 3), severe adverse events (pancreatitis or severe vomiting and hypoglycemia) prompted KD discontinuation. In another study of 12 children with fever induced refractory epileptic encephalopathy, KD was able to stop seizures within two days following ketonuria [32]. Nevertheless, the side effects of KD limit its widespread use, and successful ketosis must be attained for seizure control.
More recently, KD has been evaluated in adult patients; a systematic review of 38 adult patients with RSE or SRSE demonstrated that 82% were able to achieve SE cessation with KD [33]. There are several complex mechanisms for the efficacious effect of KD on reducing seizure activity, which result from reduction in glucose intake, ketone body production and alteration of the gut microbiome. The metabolic changes induced by KD alter the balance of excitatory and inhibitory neurotransmitters, lead to reductions in oxidative stress and systemic as well as neuroinflammation, and have further long-term effects on gene expression [3,34].
We sought KD as a rescue therapy after conventional treatments had failed.
7. Question: What Are Some Factors Should the Clinician Consider When Selecting and Initiating KD for Adults with SE?
Initiating KD Safely
Determining the optimal patient for whom to implement KD requires a comprehensive evaluation of the patient’s past medical history, comorbidities and current clinical status. As with all treatment strategies, particularly in the ICU setting, a thoughtful risk-benefit analysis is warranted. Inborn errors of metabolism are a contraindication to KD [35,36]. However, these conditions most often present in early childhood, and rarely in adults, so screening is not routinely obtained prior to KD initiation in adults [1,2]. Other contraindications of KD include unstable metabolic (mitochondrial enzyme deficiencies) conditions, liver failure, acute pancreatitis, pregnancy and an inability to tolerate enteral feeds [5]. Protocols typically avoid starting KD within 24 h of propofol infusions to avoid possibly fatal propofol infusion syndrome, characterized by metabolic acidosis, lipemia, rhabdomyolysis and myocardial failure [37].
8. Question: Should You Fast the Patient to Achieve Ketosis Quickly? If So, How Long and What Are Potential Consequences? If You Decide Not to Fast, Can Ketosis Still Be Achieved?
Variations in KD Protocols
Historically, KD implementation in the setting of childhood epilepsy included an initial fasting period ranging anywhere from 12 [7] to 48 [36,38] hours or more. Once satisfactory ketosis is achieved, ketogenic formulations or meals (typically 4:1 g of fat: carbohydrate + protein ratio) can then be titrated as tolerated until full caloric requirements are met. To avoid potential complications of a fasting period (e.g., dehydration, hypoglycemia), Kim et al. began KD without initial fasting and found equivalency in time to ketosis and seizure reduction in 41 children with intractable epilepsy compared to a retrospective control population of 83 children who fasted prior to KD initiation [39]. While rates of hypoglycemia were similar when compared to controls, there were reduced rates of dehydration and reduced length of hospital stay.
An alternative, yet equally efficacious approach for childhood epilepsy, does not involve initial fasting or limiting caloric intake. This protocol differs from others in the fact that there is a gradual increase from 1:1 to 2:1 until the goal 4:1 ratio is reached [38]. This gradual induction and establishment of ketosis in children diagnosed with intractable epilepsy showed an equal reduction in seizure activity yet decreased weight loss and episodes of hypoglycemia, acidosis and dehydration. Nevertheless, since time is a major factor in terms of avoiding neurologic and systemic consequences of SE, a more aggressive approach to KD initiation (i.e., fasting and/or more rapidly advancing to full calories as tolerated) may be warranted in this setting.
Individual patient characteristics including age, illness severity, duration of anesthetic use prior to diet initiation resulting in reduction in gastrointestinal motility, and diet complications, may not allow the luxury of initiating a preferred protocol with certain ketogenic ratio or at a faster rate. This was evident in Cobo’s pediatric SRSE study in which ratios were started as low as 0.75:1 in some instances, and ratios never exceeding 2:1 in some cases [7]. The need for higher protein intake (often in cases of poor wound healing, malnutrition and/or low basal resting energy expenditure) challenges the use of higher fat:protein + carbohydrate ratios, although this is more of a concern with chronic KD use rather than in the acute setting of RSE and SRSE. A possible way to maximize ketosis when using lower ratios (thus, higher protein intake) is the addition of medium-chain triglyceride oils as they yield greater amounts of ketones/kcal of energy than longer chain varieties [36].
We used these principles, most frequently used in the setting of childhood epilepsy, to initiate KD for our NORSE patient with the goal of achieving ketosis quickly. Our patient was initially started on KD on hospital day 28 (HD 28) with a goal of 5:1 ratio (KetoCal® 4:1 at 55 mL/h plus 33 mL medium-chain triglycerides (MCT) oil to balance carbohydrate intake from medications, documented as 51 g daily on HD 30). At this time, supplemental protein via PROsource® was discontinued to assist with achieving ketosis. On HD 35, beta-hydroxybutyrate (BHB) levels continued to show inadequate ketosis [Figure 1] prompting the increase to 6:1 with additional MCT Oil. Through HD 65, beta-hydroxybutyrate continued to fluctuate below the 2.0 goal. On HD 71, beta-hydroxybutyrate again dropped with the only documented potential carbohydrate source (at that time) being a milk and molasses enema administered by a care team to alleviate constipation. The decision was made to return to a higher carbohydrate-containing formula and refocus nutrition goals on wound healing. At this time, our patient was identified as meeting the criteria for severe malnutrition based on weight loss of >7.5% in three months and limited energy intake for greater than or equal to five days [40].
9. Question: What Factors Can Impede the Success of Achieving Ketosis, and thus Jeopardize the Utility of KD?
Despite initiating KD with complete enteral feeds on hospital day 28, our patient was only able to reach ketosis a significant 37 days later (Figure 1). After a comprehensive assessment of the care plan, the culprit was found: inconspicuous carbohydrate-containing medications, infusions and oral-care solutions routinely given in the setting of a neurological ICU (Table 2).
10. Hidden Carbohydrates Can Hinder Achievement of Ketosis
In our experience, the most likely medication-induced barriers to ketosis include sedatives, antiseizure drugs and antibiotics. Benzodiazepines are not created equally when it comes to hidden/nonobvious carbohydrate content. Diazepam (Valium® 5 mg/mL) and Lorazepam (Ativan® 2 mg/mL) have been shown to have 40% and 80% propylene glycol content, respectively, which equates to an overall carbohydrate content of 0.4 g/mL and 0.8 g/mL [42]. Intake of this carbohydrate content in patients with status epilepticus on KD may hinder achieving ketosis, but can also precipitate propylene glycol toxicity and associated anion-gap, metabolic acidosis [44].
While the carbohydrate load of each individual dose may be inconsequential, the cumulative dose given to patients in extended hospital stays may be significant. For example, initial administrations of injectable lorazepam, 2 mg every 6 h yields approximately 3 g of carbohydrate per day [44]. For context, this patient’s energy assessment used an ideal body weight of 64.5 kg, with daily caloric requirements calculated to total 2260 kcal/day (35 kcal/kg). Using KD at a 4:1 ratio (a common target for KD), the macronutrient breakdown is 226 g fat, 51.6 g protein, and 4.9 g carbohydrates. Thus, lorazepam would have contributed over half of the allotted daily carbohydrate load. Figure 1 shows several instances where lorazepam administration was associated with significant troughs in beta-hydroxybutyrate levels. When benzodiazepine infusions are warranted for refractory cases, our recommendation would be to consider midazolam as an alternative; midazolam does not have propylene glycol in its formulation, resulting in lower rates of anion-gap metabolic acidosis [45]. Regarding enteral administration of benzodiazepines, it is worth noting that clobazam (Onfi ®) and clonazepam (Klonopin®) contain 105 mg and 143.5 mg of carbohydrates (i.e., lactose, starch) per 10 mg/0.5 mg tablet, respectively [Table 2]. When selecting benzodiazepines for treatment of SE in patients treated with KD, it is important to evaluate the carbohydrate content for the selected benzodiazepine and the administration method. Generally, solutions and suspensions should be avoided due to high carbohydrate containing excipients.
Another class of widely used sedatives, often with the potential to inadvertently hinder beta-hydroxybutyrate levels, are the barbiturates, particularly pentobarbital (Nembutal® 50 mg/mL) and phenobarbital (Phenobarb® 130 mg/mL). Barbiturates are commonly used in RSE. However, they have a high propylene glycol content (pentobarbital 414 mg/50 mg vial, phenobarbital 702 mg/130 mg vial [42] amounting to an overall carbohydrate content of 2.9 g/h when pentobarbital is infused at a rate of 5 mg/kg/h for a 70 kg patient) [Table 2]. We suggest that ketamine (and midazolam, as discussed above) be considered as an alternative to pentobarbital in patients with status epilepticus on KD, given their lack of propylene glycol [46], This same concept can be applied for phenytoin (Dilantin® 50 mg/mL), which contains 40% propylene glycol [42] amounting to a carbohydrate content of 414 mg (plus an additional 79 mg of alcohol). These principles can be observed in Figure 1 where beta-hydroxybutyrate levels drop on HD 52, corresponding with a phenobarbital load (a disruption in feeds also occurred to administer phenytoin by mouth). We recommend that fosphenytoin be used instead to avoid propylene glycol excipients (Table 2). Similarly, on HD 56, beta-hydroxybutyrate dropped to 0.63 mmol/L with a medication review showing intravenous phenobarbital administered overnight. Lastly, another note of caution regarding anesthetic infusions: propofol contains 1.1 kcal/mL (mostly from fats), which provides approximately 528 kcal per day (presuming 20 mL/h). While this increased caloric load may aid in ketosis, its 450 mg of glycerol per 20 mL vial may hinder ketosis (Table 2).
11. Noncarbohydrate Related Hindrance of Ketosis
Among children with refractory epilepsy, concomitant lamotrigine use decreases KD’s efficacy in seizure reduction [47]. This may be explained by ketosis increasing the metabolism/inactivation of lamotrigine via glucosyltransferases, which ultimately results in increased glutamate release. Lastly, one must not forget that while medication use can influence KD, the inverse is also true. While most serum concentrations of ASD were not found to significantly change upon KD use, valproic acid levels have been shown to decrease [48]. Therefore, it is recommended to monitor valproic acid while using KD therapy.
12. Question: Aside from Sedative Agents, What Other Widely Used Agents in the Neurological ICU Can Hinder Ketosis?
12.1. Antimicrobials and Respective Diluents as Source of Carbohydrates
Various antibiotics that are used frequently in the neurological ICU [49,50] can hinder ketosis. Intravenous trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim®) requires reconstitution with dextrose 5% water and, similarly, vancomycin is often diluted in dextrose 5% water prior to intravenous administration (Table 2). Figure 1 (line graph) shows several instances in which administration of TMP-SMX and vancomycin were associated with troughs in beta-hydroxybutyrate levels.
12.2. Non “Medications” Contain Hidden Carbohydrates
Hidden carbohydrates are found in oral care solutions such as chlorhexidine, dietary supplements and fiber. Chlorhexidine 0.12% oral solution (PeridexTM), reported to be superior to toothbrushing at reducing early ventilator-associated pneumonia [51], contains glycerin and ethyl alcohol (see Appendix A), both carbohydrate-containing substances that can affect KD [52]. Oral fiber supplements, such as psyllium, have a significant carbohydrate load (e.g., 9 g/tablespoon) (Table 2). However, as fiber has a lower glycemic index compared to other carbohydrate-containing sources in the ICU setting, it may still be used in some instances to counteract constipation.
12.3. Comprehensive Approach to Implementing KD in Adult SE
Adopting a systematic approach is key for the successful implementation and maintenance of a ketotic state. A checklist is provided in Table 3 with a summary of the suggested steps for successful KD initiation [4].
13. Question: What Laboratory Values Should the Intensivist Pay Particular Attention to When Using KD?
Baseline assessment of certain serum (lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D, and free and total carnitine) [41] and anthropometric (weight, height) parameters [5,33,53] are imperative to effectively see how values trend overtime with KD. This objective data collected longitudinally allows monitoring of metabolic and systemic side effects of KD to allow for cessation if need-be.
After deciding that KD is appropriate, the next step is to carefully review all standing orders in the patient’s chart to identify potential sources of hidden carbohydrates and replace with alternatives. Guidance by the dietary/nutrition team as well as an ICU pharmacist are recommended to improve success with achieving and maintaining ketosis. If possible, a nutritionist with knowledge and experience with managing a KD is preferred, which may necessitate involving the pediatric nutrition team.
In the critical care setting, nutrition is often dictated by the critical care team via administration of formula tube feeding, and patient compliance is not a key factor for achieving ketosis. Route of administration does impact ketosis as suspension or elixir medications, [53] the preferred formulations via percutaneous gastrostomies (PEG) or other enteral routes, must be replaced by alternative formulations with lower carbohydrate content [7]. Additionally, dextrose-free diluents [52] must be used whenever able in intravenous drug formulations. Unavoidable carbohydrates can be balanced with a calculated dose of fat in the form of MCT oil or a commercially available emulsified oil (provided that this addition coincides with caloric and macronutrient percentages discussed later). Additionally, this puts the patient at an increased risk for gastrointestinal complications such as steatorrhea, emesis and reflux.
14. Ketosis Maintenance and Surveillance
Inducing ketosis is only the first step in tackling SE. While a ketotic state is commonly defined as beta-hydroxybutyrate >2 mmol/L [30], similarly to antiseizure drugs, some individuals require higher level of ketosis (or antiseizure drugs) to achieve optimal seizure control. Thus, individual thresholds for optimal ketotic state may vary. In the presented case, the best therapeutic effect was noted with beta-hydroxybutyrate >3.5. Maintaining ketosis above a certain therapeutic level proves to be difficult, particularly when higher targets are required such as >3 mmol/L beta-hydroxybutyrate [7]. For example, Cobo’s case series illustrated that children with SRSE can have sudden, unexplained drops in beta-hydroxybutyrate levels.
After KD was stopped on HD 73 due to poor nutritional status, KD was reinitiated on HD 106 as the patient was no longer on bolus medications with high carbohydrate content. Ketosis was achieved rapidly over two days, with a beta-hydroxybutyrate of 2.34 mmol/L target once the goal of 6:1 ratio 18 kcal/kg was reached. The rapid achievement of ketotic state likely resulted from several days of fasting prior to its initiation in the setting of percutaneous gastrostomy placement and enterocutaneous fistula repair. The patient remained in ketosis, with beta-hydroxybutyrate levels fluctuating between 1.93–5.32 mmol/L, during which time seizures were best controlled when beta-hydroxybutyrate levels were >3.5 mmol/L.
Constant evaluation and re-evaluation of patient intake, including intravenous fluids, must be conducted. It is imperative to remove all common exogenous carbohydrates including glycerin, maltodextrin, propylene glycol, dextrose, fructose, glucose, lactose, sucrose, corn syrup, sugar alcohols and starches [52]. Appropriate alternatives include normal saline, balanced crystalloid or lactated Ringer’s solution.
15. Question: What Natural Physiologic Mechanisms Must Be Accounted for When Attempting to Achieve/Maintain Ketosis?
In addition to exogenous carbohydrate management, the intensivist must not overlook endogenous perturbations of glucose homeostasis. Commonly measured anywhere from every four [54] to eight hours after initiation of KD [7], fluctuations are commonly seen in the pediatric population as the clinician attempts to titrate to a glucose target level of 60–79 mg/dL [7]. While the lower limit of 40 mg/dL is referenced in the Academy of Nutrition and Dietetics Practice Paper, the clinicians at Yale New Haven Hospital use a slightly higher limit of 50 mg/dL when evaluating for KD initiation. Ketosis can be threatened by endogenous gluconeogenesis occurring during infection or injury [55]. The topic of glucose perturbations brings up the discussion of whether the use of glucocorticoids concurrently with KD hinders the diet’s efficacy. Among children with epilepsy being treated with KD, there have been reports of glucocorticoid use (even inhaled) being associated with seizure return, elevated glucose and ketosis hindrance [56]. More studies are needed to examine the relationships of KD and glucocorticoid use in the setting of SE/RSE.
16. KD and Supplements
Question: What Supplements may Be Warranted when Starting a Ketogenic Diet?
The KD’s inherent shift into fatty acid beta-oxidation predisposes to metabolic acidosis, which can be further compounded if individuals are fasting to achieve ketosis [36]. For these reasons, adequate bicarbonate levels (commonly >17 mmol/L) [7] should be ensured with concomitant sodium bicarbonate [5] and/or potassium citrate supplementation [7].
Beta-oxidation in the mitochondria is reliant on the adequate transport of long-chain fatty acids across the mitochondrial membrane via carnitine [36,53]. Carnitine supplementation is recommended when levels are low (<30 μmol/L) or if the patient is symptomatic, defined by lethargy, weakness and GI symptoms, which are often difficult to assess in a comatose patient [7,36,53]. Carnitine supplementation remains controversial, as levels poorly correlate with tissue stores and symptoms of carnitine deficiency may be difficult to identify in comatose patients [53].
Lastly, it is recommended that a low carbohydrate multivitamin, calcium carbonate and Vitamin D be added [34,36] via nasogastric/gastric tube (NG/G-tube). Most commercially available ketogenic formulas have the recommended daily allowance of these substances. Children with epilepsy have hypovitaminosis D (50%) and are at risk for osteoporosis [36,53]. Phosphorous, [53] administered separately to avoid calcium chelation, is a recommended supplement for its role in bone homeostasis. Lastly, it is our recommendation to supplement either lite salt or table salt for patients that have hyponatremia despite administration of sodium containing intravenous fluids.
17. Termination of Ketotic Therapy
Question: Once Anesthetics Have Been Weaned and/or Seizure Activity Has Improved, How Should KD Be Weaned?
Reasons for diet discontinuation include lack of response, development of complications and need for optimization of nutritional status. There are no clear guidelines to define a clear response to KD, as diseases and patient populations are very heterogeneous, and a clear absolute seizure cessation effect may not be seen. In some cases, allowing for anesthetic wean or antiseizure regimen simplification may be considered successful results. It is our recommendation that before considering therapeutic failure, higher ketotic levels should be pursued if the patient is able to tolerate a more aggressive titration of the KD, as patients, such as our patient, may respond to higher beta-hydroxybutyrate levels.
Like any antiseizure therapy, it is generally recommended to wean the KD diet gradually due to the historical thought that abrupt withdrawal of ketosis can precipitate recurrence of seizures or SE. Abrupt withdrawal of KD is recommended for emergencies only. Thus, gradually reducing the ratio of grams of fats:protein + carbohydrates is recommended (i.e., 4:1 to 3:1 to 2:1) [36]. Despite there being a common notion that overzealous weaning of KD can precipitate previously suppressed seizure activity, a study of over 183 children showed no significant difference in the incidence of seizures worsening between discontinuation/weaning rates (i.e., <1 week vs. 1–6 weeks vs. >6 weeks) [57]. However, there was an increase in seizure activity with faster weaning schedules among a particular cohort: children who had higher percentage (55–90%) of seizure reduction while on the KD. Additionally, among children who successfully stopped KD after seizure cessation, 42% of them were unable to achieve symptom improvement with either ASD or reinitiating of KD upon seizure relapse [58].
We recommend that the clinician use the KD’s treatment success as well as clinical judgement in adopting an individualized weaning schedule. Beginning on HD 194, our patient was weaned from the KD over five days by decreasing the ketogenic formula by 20% every 24 h and replacing it with a traditional critical care formula. Supplemental MCT oil was decreased at the beginning of the weaning process. No complications arose during this transition. Once able to tolerate oral nutrition, the patient will have the autonomy to determine whether to continue KD and contingency plans, such as offering a less strict KD therapy (modified Atkins diet, modified KD), which may be a reasonable alternative.
18. Anticipating and Managing Complications
Question: What Are Some Potential Complications of KD?
Complications of KD are not uncommon and may result in discontinuation of the diet. In the pediatric literature, 30 [6] to 38% discontinuation rates [59] are described due to inability to tolerate the diet or due to complications. These complications include metabolic derangements like dyslipidemia and hyperuricemia, gastrointestinal symptoms, renal stones, osteopenia and cardiac problems like QT prolongation and cardiomyopathy [36,59]. An uncommon yet reported complication is protein-losing enteropathy [60], and while this can be corrected for by cessation of KD, the likely consequence is an increase in seizures. Like osteoporosis and Vitamin D alterations, which may not be relevant in the setting of acute KD administration for RSE, these complications are less relevant in the setting of short-term KD. Rather, more relevant complications to be aware of include dehydration, hyponatremia, metabolic acidosis, hypoglycemia, gastroparesis and nausea/vomiting [5,59].
Aside from poor wound healing and critical illness myopathy, our NORSE patient tolerated KD well and was discharged after 218 days in the hospital. Additional longitudinal studies are needed to examine long-term sequelae of a high fat diet in the context of adults with SE. Future research may focus on complication rates specifically associated with acute administration of KD for adult patients with RSE/SRSE in the neurological ICU setting, as well as cessation upon symptom improvement. Our patient’s neurological examination at discharge was significant for spontaneous eye opening, orientated x 2, minimally talkative with soft but clear speech. She was able to follow simple commands like closing her eyes and wiggle her toes. Strength was 3/5 proximal upper extremity with 2/5 in distal upper and proximal lower extremity. The patient was readmitted three weeks later for cardiac arrest, with subsequent reemergence of status epilepticus. Despite EEG improvement on restarting KD, the patient was eventually transitioned to comfort measures only.
19. Future of KD in Adult SE/RSE/SRSE/NORSE
While the utility of KD in adult populations is certainly promising for the management of RSE and SRSE, there remain several gaps, including a lack of standardized treatment approach, lack of randomized, double-blind controlled studies and hidden carbohydrate sources, which may impair production of ketone bodies. These inconspicuous carbohydrates are found in commonly administered medications for SE including benzodiazepines, antibiotics, electrolyte repletion formulations and even solutions used for oral care. This review offers a brief outline of treatment strategies for KD use in adults and a systematic approach for successfully achieving, maintaining and eliminating ketosis.
Acknowledgments
Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
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Author Contributions
Conceptualization, C.B.M., J.B.K., K.O.; Methodology, C.B.M., J.B.K., K.O.; Data Curation, C.B.M., M.C.C., L.J.H., K.O.; Writing—Original Draft Preparation, J.B.K..; Writing—Review & Editing, I.N., R.B., N.A.D., E.J.G., C.B.M.; Visualization, J.B.K., C.B.M., Supervision, C.B.M.; Project Administration, C.B.M.; Software, NA; Validation, NA; Formal analysis, NA; Investigation, NA; Resources, NA; Funding, NA. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
This report is a case study, therefore not meeting the Common Rule definition of research as it is not designed to develop generalizable knowledge and did not required ethical approval.
Informed Consent Statement
Given the retrospective nature of this report, the fatal outcome, and the lack of identifiable information, family was not contacted to obtain informed consent.
Conflicts of Interest
The authors declare no conflict of interest. Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
Appendix A
Briviact (brivaracetam injection) [package insert]. Smyrna, G. and I.R.M. UCB.
Cerebyx (fosphenytoin sodium injection) [package insert]. New York, N. and I.R.F. Pfizer.
Propofol injectable emulsion [package insert]. Lake Forest, I. and I.R.M. Hospira.
Ketalar (ketamine hydrochloride injection) [package Insert]. Chestnut Ridge, N., P. Pharmaceutical, and R.A. 2020.
Vimpat (lacosamide injection) [package insert]. Smyrna, G. and I.R.N. UCB.
Midazolam hydrochloride injection [package insert]. Lake Forest, I. and I.R. Hospira.
Thiopental sodium injection [package insert]. Galashiels, U. and L.R.O. Kyowa Kirin.
Valproate sodium injection [package insert]. Eatontown, N. and W.-W.P.C.R.M. 2019.
Sulfamethoxazole and trimethoprim injection [package insert]. Morgantown, W. and M.I.L.R.D. 2020.
Vancomycin hydrochloride for injection [package insert]. Rockford, I. and M.I.L.R.J. 2018.
Carbatrol (carbamazepine extended-release tablet) [package insert]. Lexington, M. and I.R.N. Takeda Pharmaceuticals America.
Levetiracetam immediate-release tablet [package insert]. Chestnut Ridge, N. and P.P.R.S. 2020.
Metamucil (psyllium husk powder) [product information]. Cincinnati, O. and P.G.R.D. 2019.
Divalproex sodium extended-release tablets [package insert]. Bridgewater, N. and A.P.L.R.A. 2020.
Peridex (chlorhexidine gluconate 0.12%) [package insert]. 3M Canada Company Dental Products. 2007.
Figure 1 Drug Interference with achievement of ketosis. Seizure Activity: On HD 14–16, seizure burden was 90% nonconvulsive status epilepticus (NCSE) and decreased to 10–15% by hospital day (HD) 23–24. From HD 30–39, % ictal ranged from 5–20% with HD 40 showing <1% ictal. % Ictal increased briefly during HD 41–47 with an average of 15% ictal but decreased to <1% by HD 48/49. % Ictal remained in the 10–20% range until HD 57 with % ictal < 1. From HD 58–72 % ictal ranged from 5–20% until % ictal <5 by HD 72.
jcm-10-00881-t001_Table 1Table 1 Summary work-up for New-Onset Refractory Status Epilepticus (NORSE) patient.
Categories Serum CSF Imaging Pathology
Infectious: Influenza A/B, H1N1, RPR, HIV, cat scratch panel, tick borne panel, Mycoplasma pneumonia, B Henselae, B quintana (all negative) West Nile Virus, Enterovirus, Bacterial culture, HSV, VZV, Lyme disease, fungal culture, HHV6, EBV, Mycoplasma pneumoniae (all negative)
Inflammatory: ANA, dsDNA, SSA, SSB, SCL 70, CRP, ESR, TPO antibody, thyroglobulin antibody, complements (C3, C4, CH50), ANCA, B2 glycoprotein, anticardiolipin, Antiribosomal P protein Ab, ACE, smooth muscle antibody, skeletal muscle antibody AMPA-R Ab, CASPR2 Ab, DPPX Ab, GABA-B-R Ab, GAD 65, GFAP, LGI1-IgG, mGluR1 Ab, NMDA R Ab
Paraneoplastic: GAD 65, NMDA, voltage gated potassium channel antibody, flow cytometry AChR ganglionic neuronal Ab, Amphiphysin Ab, Antiglial nuclear Ab, Antineuronal nuclear Ab, CRMP-5, Neuronal (V-G) K+ channel Ab, N-Type Calcium channel ab, P/Q type calcium channel Ab, Purkinje cell cytoplasmic Ab, Striational Ab (all negative)
Metabolic: TSH (0.22), Free T4 (1.7 ng/dL), Ammonia (47, 33, 37 µL/dL), serum and urine toxicology (negative)
MRI brain w/wo contrast: restricted diffusion and hyperintense FLAIR signal in the bilateral hippocampi Benign ovarian cyst
CT Chest/abdomen/pelvis: no evidence of ovarian teratoma or other malignancy No malignant cells in CSF
US pelvis: tiny 3–4 mm echogenic focus on the left ovary which may represent a small calcification, however, a tiny teratoma cannot be excluded
MRI pelvis: no evidence of ovarian teratoma
Work-up recommendations from Table 1 from Sculier C, Gaspard N. New onset refractory status epilepticus (NORSE). Seizure. 2019 May; 68:72–78. doi: 10.1016/j.seizure.2018.09.018. Epub 2018 Sep 29. PMID: 30482654. [18]. Influenza A/B: negative; H1N1: negative; Smooth and skeletal muscle antibody: negative; RPR: rapid plasma reagent—negative; ANA: antinuclear antibody—1:2560 titer; dsDNA: double-strand DNA—positive, 38.4 IU/mL; SSA: Sjögren’s Syndrome A—greater than 8; SSB: Sjögren’s Syndrome B—negative; SCL 70: Scleroderma (antitopoisomerase)—negative; Antiribosomal P protein—negative; CRP: C-reactive protein—54 mg/L; ESR: erythrocyte sedimentation rate—51 mm/h; C3/C4/CH50: within normal limits; B2 glycoprotein—negative; Anticardiolipin—negative; TPO: thyroperoxidase antibody—negative; thyroglobulin antibody—negative; ANCA: antineutrophil cytoplasmic antibody—negative; ACE: angiotensin converting enzyme—within normal limits; GAD 65: Glutamic acid decarboxylase—negative; NMDA: N-methyl-D-Aspartate receptor antibody—negative; AMPA: α-amino-3-hydroxy-5-methyl-4 -isoxazolepropionic acid receptor- antibody negative; TSH: thyroid stimulating hormone—within normal limits; HIV: Human immunodeficiency virus—negative; Lyme disease—negative; West Nile Virus—negative; Enterovirus- negative; Bacterial and fungal culture—negative; HSV: Herpes Simplex Virus—negative; VZV: Varicella Zoster Virus—negative; HHV6: Human Herpes Virus 6—negative; EBV: Epstein Barr Virus—negative; GFAP: Glial Fibrillary Acidic Protein—negative; LGI1: Leucine-rich glioma-inactivated—negative; CASPR2: Contactin-associated protein-like 2—negative; DPPX: dipeptidyl-peptidase-like protein 6—negative; GABA: gamma-aminobutyric acid—negative; mGlu1: metabotropic glutamate receptor 1—negative; CRMP-5: CV2/collapsin response mediator protein—negative; Voltage gated potassium channel—negative.
jcm-10-00881-t002_Table 2Table 2 Common antiseizure medications, medications utilized in hospitalized patients and associated carbohydrate, fat, and alcohol content.
Intravenous Product (General Product Concentration)
Carbohydrate Excipient and Amount Per Vial
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Brivaracetam (10 mg/mL) – – – –
Diazepam (5 mg/mL) [41] Propylene glycol: 414 mg 828 mg CHO/10 mg – 79 mg
Famotidine (10 mg/mL) [41] Mannitol: 20 mg 40 mg CHO/40 mg – –
Fosphenytoin [42] – – – –
Lorazepam (2 mg/mL) [42] Propylene glycol: 753 mg – – –
Pentobarbital (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Phenobarbital (130 mg/mL) [41] Propylene glycol: 702 mg – – 79 mg
Phenytoin (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Propofol (10 mg/mL) [41] Glycerol: 22.5 mg/mL 450 mg CHO/h
(20 mL/h) Soybean oil: 100 mg/mL Benzyl alcohol *
Egg Lecithin: 12 mg/mL
Lipid: 100 mg/mL
(1.1 kcal/mL)
Ketamine (multiple) – – – –
Lacosamide (multiple) – – – –
Midazolam (multiple) – – – Benzyl alcohol †
Thiopental (25 mg/mL) – – – –
Valproate (20 mg/mL) – – – –
Trimethoprim-sulfamethoxazole (Bactrim®) diluted in Dextrose 5% W 100 mL per 80–400 mg TMP-SMX Dextrose: 5 g/100 ml Up to 20 g CHO per dose – –
Vancomycin (Vancocin®) diluted in Dextrose 5% W per 1 g/250 mL solution Dextrose: 5 g/100 ml Up to 2 g CHO per dose – –
Enteral Product § (General Product Strength)
Carbohydrate Excipient and Amount Per Unit
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Carbamazepine (extended-release tablet) Lactose monohydrate ‡
Microcrystalline cellulose ‡ – – –
Clobazam (10 mg tablet) [43] 105.3 mg/tablet ≈100 mg/10 mg – –
Clonazepam (0.5 mg tablet) [43] 143.5 mg/tablet ≈2800 mg/10 mg – –
Levetiracetam (immediate release tablet) Croscarmellose sodium ‡
Polyethylene glycol 3350 ‡
Polyethylene glycol 6000 ‡ – – Polyvinyl alcohol
Psyllium (Metamucil) packet 9 g CHO/tablespoon 27 g CHO/day (TID) – –
Divalproex sodium (extended-release tablet) Hypromelloses ‡
Lactose monohydrate ‡
Polyethylene glycol ‡
Propylene glycol ‡
Macrogol ‡
Microcrystalline cellulose ‡ – – n-Butyl alcohol
Isopropyl alcohol
Polyvinyl alcohol
See Appendix A for package inserts. * Present at 1.5 mg/mL in all vial sizes (0.15% w/v). Avoid use in pediatric populations due to benzyl alcohol content. † Present at 10 mg/mL in all vial sizes (1% w/v), except preservative-free formulations. Avoid use in pediatric populations due to benzyl alcohol content. ‡ Unknown amount of relative excipient may affect ketosis but is likely clinically insignificant. § Solution and suspension formulations should be avoided if possible as they usually contain sugars that will affect ketosis.
jcm-10-00881-t003_Table 3Table 3 Ketogenic Diet checklist for Status Epilepticus.
Pearls to Consider for Starting and Maintaining a Ketogenic Diet (KD)
I. KD initiation
○ Check fasting lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D serum levels
○ Record baseline weight and height
○ Continuous video EEG
○ Dietitian/nutrition consult (consider pediatric nutritionist)
○ Stop current enteral formula
○ Reduce carbohydrate content in medications and parenteral fluids with pharmacy input
○ Active communication with nursing/pharmacy, EMR warnings, and signs in room are crucial to avoid medication/IV-containing carbohydrates
○ Begin KD (e.g., KetoCal/MCT oil)
○ Include multivitamin injection, Vit. D and calcium supplementation via nasogastric tube/gastric tube
○ Change any oral agents from liquid formulation to crushed tablet formulation
II. KD maintenance
○ Remove all common carbohydrate excipients in intravenous fluids, including:
○ Glycerin
○ Maltodextrin
○ Propylene glycol
○ Sugars (dextrose, fructose, glucose, lactose, sucrose, corn syrup)
○ Sugar alcohols (glycerol, mannitol, sorbitol)
○ Starches
○
KD can be challenged via coadministration of other meds & IVs!
III. Pitfalls to consider:
○ Contraindications: unstable metabolic derangements, hemodynamic instability, coagulopathy/bleeding diathesis, pancreatitis, liver failure, severe hyperlipidemia, ileus, pregnancy, known fatty acid oxidation disorder or pyruvate carboxylase deficiency
○
Propofol infusions cannot be given within 24 h before starting a KD!
Adapted & modified from Table 3 from Thakur KT, Probasco JC, Hocker SE, et al. Neurology. 2014 Feb 25; 82(8): 665–670. [4]. | ACYCLOVIR, LEVETIRACETAM, LORAZEPAM, PENTOBARBITAL, PHENYTOIN, PROPOFOL, VALPROIC ACID | DrugsGivenReaction | CC BY | 33671485 | 19,466,490 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Seizure'. | Pearls and Pitfalls of Introducing Ketogenic Diet in Adult Status Epilepticus: A Practical Guide for the Intensivist.
Background: Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of a ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and effective. Methods: We describe our experience, including the challenges of achieving and maintaining ketosis, in an adult with new onset refractory status epilepticus (NORSE). Case Vignette: A previously healthy 29-year-old woman was admitted with cryptogenic NORSE following a febrile illness; course was complicated by prolonged super-refractory SE. A comprehensive work-up was notable only for mild cerebral spinal fluid (CSF) pleocytosis, elevated nonspecific serum inflammatory markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI). Repeat CSF testing was normal and serial MRIs demonstrated resolution of edema and diffusion restriction with progressive hippocampal and diffuse atrophy. She required prolonged therapeutic coma with high anesthetic infusion rates, 16 antiseizure drug (ASD) trials, empiric immunosuppression and partial bilateral oophorectomy. Enteral ketogenic formula was started on hospital day 28. However, sustained beta-hydroxybutyrate levels >2 mmol/L were only achieved 37 days later following a comprehensive adjustment of the care plan. KD was challenging to maintain in the intensive care unit (ICU) and was discontinued due to poor nutritional state and pressure ulcers. KD was restarted again in a non-ICU unit facilitating ASD tapering without re-emergence of SE. Discussion: There are inconspicuous carbohydrates in commonly administered medications for SE including antibiotics, electrolyte repletion formulations, different preparations of the same drug (i.e., parenteral, tablet, or suspension) and even solutions used for oral care-all challenging the use of KD in the hospitalized patient. Tailoring comprehensive care and awareness of possible complications of KD are important for the successful implementation and maintenance of ketosis.
1. Introduction
Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and potentially effective [1,2,3,4,5]. Most often used in childhood epilepsies, KD has emerged as a potential adjunctive treatment for pediatric SE [6,7]. We describe our experience with an adult with new onset refractory status epilepticus (NORSE) focusing on the unexpected challenge of achieving and maintaining ketosis. Practical advice, and a comprehensive review of factors potentially jeopardizing ketosis commonly encountered in the critical care setting and alternatives are provided.
2. Presentation
A previously healthy 29-year-old woman was admitted to another institution with new onset refractory status epilepticus (NORSE) following a febrile illness with a course complicated by prolonged super-refractory SE. Three days prior to presentation she developed fever, headache, emesis and fatigue in the setting of being in contact with her child with an upper respiratory tract infection. On the morning of admission, her friend attempted to awaken her for work and found her unresponsive and convulsing. In the emergency department, she was lethargic and mumbling incoherently. During her initial evaluation she had a witnessed 45-s bilateral tonic-clonic seizure that was aborted with 2 mg lorazepam intravenously. Head computed tomography was unremarkable and initial cerebrospinal fluid (CSF) analysis showed a mononuclear pleocytosis (2 RBC, 41 nucleated cells (57% mononuclear cells), glucose 93, protein 54)). A one-hour electroencephalogram (EEG) showed diffuse delta activity admixed with sleep spindles and K complexes without epileptiform discharges. She was monitored in the step-down unit and treated with levetiracetam and acyclovir. On hospital day two, she was somnolent but arousable to voice; she was able to follow simple midline commands, state her name and the current president, but was disoriented to time. She was noted to have twitching of her face, but no EEG was done at that time. By hospital day three, she began experiencing brief convulsive seizures which were aborted with intravenous lorazepam and always associated with recovery of consciousness. At that point, phenytoin (1 g loading dose, maintenance at 100 mg q8h) was added to her antiseizure drug (ASD) regimen. On hospital day four, she had multiple convulsive seizures without return to baseline, complicated by acute hypoxic respiratory failure requiring intubation. She was transferred to the intensive care unit (ICU) where she was started on propofol, and valproic acid (20 mg/kg loading dose, maintenance at 750 mg Q8H) was added. Routine EEG captured multiple discrete right frontal and centrotemporal onset seizures correlating with episodes of face twitching. She was started on pentobarbital infusion (5 mg/kg bolus, maintenance at 1 mg/kg per hour) and transferred to our center for continuous EEG monitoring.
3. Question: How Is Prolonged Seizure Activity Classified and What Are Potential Etiologies to Be Considered?
According to the most recent classification set by The International League Against Epilepsy, SE is a “condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures” [8]. While operational SE definitions based on time-domains vary according to seizure type, it is generally accepted that convulsive seizure activity lasting either greater than 5 min continuously, or two or more seizures during which the individual does not recover to baseline between seizures, represents SE [8]. Inhibitory gamma-aminobutyric acid (GABA) neurons located in the pars reticulata of the substantia nigra are key in seizure termination [9]. During status epilepticus, marked alteration of GABA metabolism occurs in this region and results in disinhibition of excitatory pathways: GABA synthesis slows down [10]. GABA turnover time increases up to three-fold, [10] and GABA receptors (originally located in the surface of the cell membrane) migrate to the intracellular space within minutes of ongoing seizure activity [11,12,13]. Prompt initiation of abortive therapies is key, as the internalization of GABA receptors contributes to refractoriness to treatment.
Emergent administration of parenteral benzodiazepine (e.g., up to 0.1 mg/kg of lorazepam) is considered the first-line therapy for SE [14]. If a patient fails to respond to a benzodiazepine and a second appropriately selected and dosed ASD at adequate doses, they are in refractory status epilepticus (RSE). It has been reported that one in five RSE patients go on to develop super-refractory status epilepticus (SRSE), defined as (1) ongoing seizures lasting 24 h or more after onset of anesthetic therapy (i.e., propofol) or (2) recurrence of SE upon reduction or withdrawal of therapeutic anesthetic coma [15]. The clinical presentation of RSE in patients without overt acute or remote brain injury, prior epilepsy, or acute toxic/metabolic explanation is consistent with New Onset Refractory Status Epilepticus—NORSE [16]. Febrile Infection-Related Epilepsy Syndrome (FIRES) is a subset of NORSE, in which a febrile infectious illness precedes SE onset by 1–14 days [14,15,16]. Thus, our patient qualified as having the syndrome of FIRES as well as NORSE. Further, clinical criteria for unequivocal electroencephalographic status epilepticus in patients without known epileptic encephalopathy has been established in the Salzburg consensus: (1) repeating epileptiform discharges occurring >2.5 Hz, or (2) repeating epileptiform discharges occurring ≤2.5 Hz or rhythmic delta/theta activity >0.5 Hz plus (a) electroclinical response (improvement) following intravenous ASD challenge, (b) subtle clinical correlate associated with pattern, or (c) typical temporal and spatial evolution of pattern [17].
Determining the underlying etiology of SE may seem a daunting task. However, its importance in achieving seizure cessation cannot be underestimated. Outcome following SE is dependent on the etiology of seizures. Further, appropriately recognizing the electroclinical classification of seizures (i.e., identifying the seizure semiology and its electrographic signature) may not only help selection of therapy but also identify potential etiologies [8]. Among NORSE patients, an etiology is found in up to 50% of cases [16]. Of those with an identifiable cause, the majority (37%) had an autoimmune cause (both nonparaneoplatic and paraneoplastic), while 8% had a probable infectious cause [16]. Thus, if an autoimmune etiology is diagnosed or clinically suspected, immune modulating therapies such as high-dose corticosteroids, intravenous immunoglobulin (IVIg) or plasma exchange therapy, followed by monoclonal antibodies and/or interleukin inhibitors, should be considered early in the course.
Our patient underwent a comprehensive work-up to determine the etiology of NORSE, as summarized on Table 1, which was notable only for mild CSF pleocytosis, elevated nonspecific inflammatory serum markers and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI).
4. Question: What Are the Initial Steps in the Therapeutic Algorithm for Status Epilepticus?
Benzodiazepines are the first-line treatment for SE [14,19] with slower-acting, less sedating parenteral ASDs being the second line (e.g., phenytoin, fosphenytoin, valproate and levetiracetam; and possibly lacosamide and phenobarbital). The Established Status Epilepticus Treatment Trial (ESETT) found no difference in efficacy between fosphenytoin (20 mgPE/kg), valproate (40 mg/kg) and levetiracetam (60 mg/kg) in children, adults and older adults; these ASDs were able to abort SE within an hour in nearly 50% of patients [20]. Once the second-line, or a combination of medications, fails to result in seizure cessation, continuous intravenous infusions of anesthetics (i.e., midazolam, pentobarbital, propofol, ketamine) are often recommended [14,19].
In patients with SE, anesthetic use is associated with longer hospital stay, but not in-hospital or 90-day mortality [21]. Amongst NORSE patients who receive anesthetics, the mortality is high. However, the use of anesthetics is not associated with poor outcome [16]. In 61 patients with RSE, those who underwent deep sedation (defined as either EEG showing burst suppression or isoelectric activity) had both poorer long-term prognosis and increased mortality [22]. Burst suppression on EEG is defined as intermittent alternating periods of low amplitudes (<10 uV for burst suppression; 10–20 uV for burst attenuation) interrupting a background, which may consist of waves of varying frequencies. Earlier attainment of burst suppression may allow for a more rapid anesthetic wean [23], and it is important to frequently monitor the EEG and titrate anesthetic dose as appropriate. The goal of anesthetic use in RSE is the resolution of epileptiform activity in order to avoid physiologic effects while the underlying cause is identified and treated [24,25].
In our case, 16 antiseizure drug trials in various combinations and high anesthetic infusion rates were attempted. RSE persisted despite 160 mg/h (2.5 mg/kg/h) of midazolam prompting the initiation of ketamine. Despite improved seizure burden following ketamine bolus (1.5 mg/kg), reemergence of SE occurred despite up-titration of ketamine to our maximum infusion rate (7.5 mg/kg/h). Her EEG responded to propofol and pentobarbital with long periods of suppression, although her background remained with abundant generalized periodic discharges (GPD) at 2.5–3 Hz, qualifying as ongoing electrographic SE. [17,26] Burst suppression was eventually achieved with pentobarbital at 3 mg/kg/h and propofol at 40 mcg/kg/min. However, due to re-emergence of 2 Hz GPDs along with breakthrough seizures on attempted wean, she remained in a medically induced coma for over three months.
5. Question: What Are Potential Rescue Therapeutic Approaches to the Management of Super-Refractory Status Epilepticus?
Refractory and super-refractory SE and their complications are associated with significant morbidity including death, neuronal damage and systemic complications like cardiomyopathy, ischemic bowel, pulmonary edema and renal failure [27]. This highlights the necessity for a prompt and aggressive treatment approach. In the setting of treatment failure, alternative treatment options include inhaled anesthetics, magnesium infusion, pyridoxine, hypothermia, electrical and magnetic stimulation, additional immunotherapy, enteral ASDs and the KD [28].
Given a high suspicion for an autoimmune process, our patient was treated with intravenous methylprednisolone (1 g daily for 5 days), IVIg, plasma exchange and cyclophosphamide. Serial MRIs demonstrated resolution of edema and diffusion restriction with gradually progressive atrophy, predominantly in the hippocampi, and repeat CSF analysis was normal. She underwent empiric bilateral partial oophorectomy for an echogenic focus in her left ovary and concern for possible occult microteratoma, possibly secondary to N-methyl-D-Aspartate (NMDA) encephalitis (NMDA CSF < 1:1 and serum < 1:10) [29].
6. Ketogenic Diet
Ketosis is commonly defined as sustained beta-hydroxybutyrate levels > 2 mmol/L [30] or a urinary acetoacetate level of >40 mg/dL [31]. There is evidence supporting the use of KD in children with autoimmune epilepsies, symptomatic epilepsy syndromes, pediatric refractory and super-refractory SE [6,32]. In a study of 10 children (age six months—16 years old) with refractory focal SE, initiation of a KD resulted in lower seizure burden (50% reduction in seizures for 70% of the cohort) and resolution of seizures in 20% [6]. In the minority of patients with less than 50% seizure reduction (n = 3), severe adverse events (pancreatitis or severe vomiting and hypoglycemia) prompted KD discontinuation. In another study of 12 children with fever induced refractory epileptic encephalopathy, KD was able to stop seizures within two days following ketonuria [32]. Nevertheless, the side effects of KD limit its widespread use, and successful ketosis must be attained for seizure control.
More recently, KD has been evaluated in adult patients; a systematic review of 38 adult patients with RSE or SRSE demonstrated that 82% were able to achieve SE cessation with KD [33]. There are several complex mechanisms for the efficacious effect of KD on reducing seizure activity, which result from reduction in glucose intake, ketone body production and alteration of the gut microbiome. The metabolic changes induced by KD alter the balance of excitatory and inhibitory neurotransmitters, lead to reductions in oxidative stress and systemic as well as neuroinflammation, and have further long-term effects on gene expression [3,34].
We sought KD as a rescue therapy after conventional treatments had failed.
7. Question: What Are Some Factors Should the Clinician Consider When Selecting and Initiating KD for Adults with SE?
Initiating KD Safely
Determining the optimal patient for whom to implement KD requires a comprehensive evaluation of the patient’s past medical history, comorbidities and current clinical status. As with all treatment strategies, particularly in the ICU setting, a thoughtful risk-benefit analysis is warranted. Inborn errors of metabolism are a contraindication to KD [35,36]. However, these conditions most often present in early childhood, and rarely in adults, so screening is not routinely obtained prior to KD initiation in adults [1,2]. Other contraindications of KD include unstable metabolic (mitochondrial enzyme deficiencies) conditions, liver failure, acute pancreatitis, pregnancy and an inability to tolerate enteral feeds [5]. Protocols typically avoid starting KD within 24 h of propofol infusions to avoid possibly fatal propofol infusion syndrome, characterized by metabolic acidosis, lipemia, rhabdomyolysis and myocardial failure [37].
8. Question: Should You Fast the Patient to Achieve Ketosis Quickly? If So, How Long and What Are Potential Consequences? If You Decide Not to Fast, Can Ketosis Still Be Achieved?
Variations in KD Protocols
Historically, KD implementation in the setting of childhood epilepsy included an initial fasting period ranging anywhere from 12 [7] to 48 [36,38] hours or more. Once satisfactory ketosis is achieved, ketogenic formulations or meals (typically 4:1 g of fat: carbohydrate + protein ratio) can then be titrated as tolerated until full caloric requirements are met. To avoid potential complications of a fasting period (e.g., dehydration, hypoglycemia), Kim et al. began KD without initial fasting and found equivalency in time to ketosis and seizure reduction in 41 children with intractable epilepsy compared to a retrospective control population of 83 children who fasted prior to KD initiation [39]. While rates of hypoglycemia were similar when compared to controls, there were reduced rates of dehydration and reduced length of hospital stay.
An alternative, yet equally efficacious approach for childhood epilepsy, does not involve initial fasting or limiting caloric intake. This protocol differs from others in the fact that there is a gradual increase from 1:1 to 2:1 until the goal 4:1 ratio is reached [38]. This gradual induction and establishment of ketosis in children diagnosed with intractable epilepsy showed an equal reduction in seizure activity yet decreased weight loss and episodes of hypoglycemia, acidosis and dehydration. Nevertheless, since time is a major factor in terms of avoiding neurologic and systemic consequences of SE, a more aggressive approach to KD initiation (i.e., fasting and/or more rapidly advancing to full calories as tolerated) may be warranted in this setting.
Individual patient characteristics including age, illness severity, duration of anesthetic use prior to diet initiation resulting in reduction in gastrointestinal motility, and diet complications, may not allow the luxury of initiating a preferred protocol with certain ketogenic ratio or at a faster rate. This was evident in Cobo’s pediatric SRSE study in which ratios were started as low as 0.75:1 in some instances, and ratios never exceeding 2:1 in some cases [7]. The need for higher protein intake (often in cases of poor wound healing, malnutrition and/or low basal resting energy expenditure) challenges the use of higher fat:protein + carbohydrate ratios, although this is more of a concern with chronic KD use rather than in the acute setting of RSE and SRSE. A possible way to maximize ketosis when using lower ratios (thus, higher protein intake) is the addition of medium-chain triglyceride oils as they yield greater amounts of ketones/kcal of energy than longer chain varieties [36].
We used these principles, most frequently used in the setting of childhood epilepsy, to initiate KD for our NORSE patient with the goal of achieving ketosis quickly. Our patient was initially started on KD on hospital day 28 (HD 28) with a goal of 5:1 ratio (KetoCal® 4:1 at 55 mL/h plus 33 mL medium-chain triglycerides (MCT) oil to balance carbohydrate intake from medications, documented as 51 g daily on HD 30). At this time, supplemental protein via PROsource® was discontinued to assist with achieving ketosis. On HD 35, beta-hydroxybutyrate (BHB) levels continued to show inadequate ketosis [Figure 1] prompting the increase to 6:1 with additional MCT Oil. Through HD 65, beta-hydroxybutyrate continued to fluctuate below the 2.0 goal. On HD 71, beta-hydroxybutyrate again dropped with the only documented potential carbohydrate source (at that time) being a milk and molasses enema administered by a care team to alleviate constipation. The decision was made to return to a higher carbohydrate-containing formula and refocus nutrition goals on wound healing. At this time, our patient was identified as meeting the criteria for severe malnutrition based on weight loss of >7.5% in three months and limited energy intake for greater than or equal to five days [40].
9. Question: What Factors Can Impede the Success of Achieving Ketosis, and thus Jeopardize the Utility of KD?
Despite initiating KD with complete enteral feeds on hospital day 28, our patient was only able to reach ketosis a significant 37 days later (Figure 1). After a comprehensive assessment of the care plan, the culprit was found: inconspicuous carbohydrate-containing medications, infusions and oral-care solutions routinely given in the setting of a neurological ICU (Table 2).
10. Hidden Carbohydrates Can Hinder Achievement of Ketosis
In our experience, the most likely medication-induced barriers to ketosis include sedatives, antiseizure drugs and antibiotics. Benzodiazepines are not created equally when it comes to hidden/nonobvious carbohydrate content. Diazepam (Valium® 5 mg/mL) and Lorazepam (Ativan® 2 mg/mL) have been shown to have 40% and 80% propylene glycol content, respectively, which equates to an overall carbohydrate content of 0.4 g/mL and 0.8 g/mL [42]. Intake of this carbohydrate content in patients with status epilepticus on KD may hinder achieving ketosis, but can also precipitate propylene glycol toxicity and associated anion-gap, metabolic acidosis [44].
While the carbohydrate load of each individual dose may be inconsequential, the cumulative dose given to patients in extended hospital stays may be significant. For example, initial administrations of injectable lorazepam, 2 mg every 6 h yields approximately 3 g of carbohydrate per day [44]. For context, this patient’s energy assessment used an ideal body weight of 64.5 kg, with daily caloric requirements calculated to total 2260 kcal/day (35 kcal/kg). Using KD at a 4:1 ratio (a common target for KD), the macronutrient breakdown is 226 g fat, 51.6 g protein, and 4.9 g carbohydrates. Thus, lorazepam would have contributed over half of the allotted daily carbohydrate load. Figure 1 shows several instances where lorazepam administration was associated with significant troughs in beta-hydroxybutyrate levels. When benzodiazepine infusions are warranted for refractory cases, our recommendation would be to consider midazolam as an alternative; midazolam does not have propylene glycol in its formulation, resulting in lower rates of anion-gap metabolic acidosis [45]. Regarding enteral administration of benzodiazepines, it is worth noting that clobazam (Onfi ®) and clonazepam (Klonopin®) contain 105 mg and 143.5 mg of carbohydrates (i.e., lactose, starch) per 10 mg/0.5 mg tablet, respectively [Table 2]. When selecting benzodiazepines for treatment of SE in patients treated with KD, it is important to evaluate the carbohydrate content for the selected benzodiazepine and the administration method. Generally, solutions and suspensions should be avoided due to high carbohydrate containing excipients.
Another class of widely used sedatives, often with the potential to inadvertently hinder beta-hydroxybutyrate levels, are the barbiturates, particularly pentobarbital (Nembutal® 50 mg/mL) and phenobarbital (Phenobarb® 130 mg/mL). Barbiturates are commonly used in RSE. However, they have a high propylene glycol content (pentobarbital 414 mg/50 mg vial, phenobarbital 702 mg/130 mg vial [42] amounting to an overall carbohydrate content of 2.9 g/h when pentobarbital is infused at a rate of 5 mg/kg/h for a 70 kg patient) [Table 2]. We suggest that ketamine (and midazolam, as discussed above) be considered as an alternative to pentobarbital in patients with status epilepticus on KD, given their lack of propylene glycol [46], This same concept can be applied for phenytoin (Dilantin® 50 mg/mL), which contains 40% propylene glycol [42] amounting to a carbohydrate content of 414 mg (plus an additional 79 mg of alcohol). These principles can be observed in Figure 1 where beta-hydroxybutyrate levels drop on HD 52, corresponding with a phenobarbital load (a disruption in feeds also occurred to administer phenytoin by mouth). We recommend that fosphenytoin be used instead to avoid propylene glycol excipients (Table 2). Similarly, on HD 56, beta-hydroxybutyrate dropped to 0.63 mmol/L with a medication review showing intravenous phenobarbital administered overnight. Lastly, another note of caution regarding anesthetic infusions: propofol contains 1.1 kcal/mL (mostly from fats), which provides approximately 528 kcal per day (presuming 20 mL/h). While this increased caloric load may aid in ketosis, its 450 mg of glycerol per 20 mL vial may hinder ketosis (Table 2).
11. Noncarbohydrate Related Hindrance of Ketosis
Among children with refractory epilepsy, concomitant lamotrigine use decreases KD’s efficacy in seizure reduction [47]. This may be explained by ketosis increasing the metabolism/inactivation of lamotrigine via glucosyltransferases, which ultimately results in increased glutamate release. Lastly, one must not forget that while medication use can influence KD, the inverse is also true. While most serum concentrations of ASD were not found to significantly change upon KD use, valproic acid levels have been shown to decrease [48]. Therefore, it is recommended to monitor valproic acid while using KD therapy.
12. Question: Aside from Sedative Agents, What Other Widely Used Agents in the Neurological ICU Can Hinder Ketosis?
12.1. Antimicrobials and Respective Diluents as Source of Carbohydrates
Various antibiotics that are used frequently in the neurological ICU [49,50] can hinder ketosis. Intravenous trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim®) requires reconstitution with dextrose 5% water and, similarly, vancomycin is often diluted in dextrose 5% water prior to intravenous administration (Table 2). Figure 1 (line graph) shows several instances in which administration of TMP-SMX and vancomycin were associated with troughs in beta-hydroxybutyrate levels.
12.2. Non “Medications” Contain Hidden Carbohydrates
Hidden carbohydrates are found in oral care solutions such as chlorhexidine, dietary supplements and fiber. Chlorhexidine 0.12% oral solution (PeridexTM), reported to be superior to toothbrushing at reducing early ventilator-associated pneumonia [51], contains glycerin and ethyl alcohol (see Appendix A), both carbohydrate-containing substances that can affect KD [52]. Oral fiber supplements, such as psyllium, have a significant carbohydrate load (e.g., 9 g/tablespoon) (Table 2). However, as fiber has a lower glycemic index compared to other carbohydrate-containing sources in the ICU setting, it may still be used in some instances to counteract constipation.
12.3. Comprehensive Approach to Implementing KD in Adult SE
Adopting a systematic approach is key for the successful implementation and maintenance of a ketotic state. A checklist is provided in Table 3 with a summary of the suggested steps for successful KD initiation [4].
13. Question: What Laboratory Values Should the Intensivist Pay Particular Attention to When Using KD?
Baseline assessment of certain serum (lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D, and free and total carnitine) [41] and anthropometric (weight, height) parameters [5,33,53] are imperative to effectively see how values trend overtime with KD. This objective data collected longitudinally allows monitoring of metabolic and systemic side effects of KD to allow for cessation if need-be.
After deciding that KD is appropriate, the next step is to carefully review all standing orders in the patient’s chart to identify potential sources of hidden carbohydrates and replace with alternatives. Guidance by the dietary/nutrition team as well as an ICU pharmacist are recommended to improve success with achieving and maintaining ketosis. If possible, a nutritionist with knowledge and experience with managing a KD is preferred, which may necessitate involving the pediatric nutrition team.
In the critical care setting, nutrition is often dictated by the critical care team via administration of formula tube feeding, and patient compliance is not a key factor for achieving ketosis. Route of administration does impact ketosis as suspension or elixir medications, [53] the preferred formulations via percutaneous gastrostomies (PEG) or other enteral routes, must be replaced by alternative formulations with lower carbohydrate content [7]. Additionally, dextrose-free diluents [52] must be used whenever able in intravenous drug formulations. Unavoidable carbohydrates can be balanced with a calculated dose of fat in the form of MCT oil or a commercially available emulsified oil (provided that this addition coincides with caloric and macronutrient percentages discussed later). Additionally, this puts the patient at an increased risk for gastrointestinal complications such as steatorrhea, emesis and reflux.
14. Ketosis Maintenance and Surveillance
Inducing ketosis is only the first step in tackling SE. While a ketotic state is commonly defined as beta-hydroxybutyrate >2 mmol/L [30], similarly to antiseizure drugs, some individuals require higher level of ketosis (or antiseizure drugs) to achieve optimal seizure control. Thus, individual thresholds for optimal ketotic state may vary. In the presented case, the best therapeutic effect was noted with beta-hydroxybutyrate >3.5. Maintaining ketosis above a certain therapeutic level proves to be difficult, particularly when higher targets are required such as >3 mmol/L beta-hydroxybutyrate [7]. For example, Cobo’s case series illustrated that children with SRSE can have sudden, unexplained drops in beta-hydroxybutyrate levels.
After KD was stopped on HD 73 due to poor nutritional status, KD was reinitiated on HD 106 as the patient was no longer on bolus medications with high carbohydrate content. Ketosis was achieved rapidly over two days, with a beta-hydroxybutyrate of 2.34 mmol/L target once the goal of 6:1 ratio 18 kcal/kg was reached. The rapid achievement of ketotic state likely resulted from several days of fasting prior to its initiation in the setting of percutaneous gastrostomy placement and enterocutaneous fistula repair. The patient remained in ketosis, with beta-hydroxybutyrate levels fluctuating between 1.93–5.32 mmol/L, during which time seizures were best controlled when beta-hydroxybutyrate levels were >3.5 mmol/L.
Constant evaluation and re-evaluation of patient intake, including intravenous fluids, must be conducted. It is imperative to remove all common exogenous carbohydrates including glycerin, maltodextrin, propylene glycol, dextrose, fructose, glucose, lactose, sucrose, corn syrup, sugar alcohols and starches [52]. Appropriate alternatives include normal saline, balanced crystalloid or lactated Ringer’s solution.
15. Question: What Natural Physiologic Mechanisms Must Be Accounted for When Attempting to Achieve/Maintain Ketosis?
In addition to exogenous carbohydrate management, the intensivist must not overlook endogenous perturbations of glucose homeostasis. Commonly measured anywhere from every four [54] to eight hours after initiation of KD [7], fluctuations are commonly seen in the pediatric population as the clinician attempts to titrate to a glucose target level of 60–79 mg/dL [7]. While the lower limit of 40 mg/dL is referenced in the Academy of Nutrition and Dietetics Practice Paper, the clinicians at Yale New Haven Hospital use a slightly higher limit of 50 mg/dL when evaluating for KD initiation. Ketosis can be threatened by endogenous gluconeogenesis occurring during infection or injury [55]. The topic of glucose perturbations brings up the discussion of whether the use of glucocorticoids concurrently with KD hinders the diet’s efficacy. Among children with epilepsy being treated with KD, there have been reports of glucocorticoid use (even inhaled) being associated with seizure return, elevated glucose and ketosis hindrance [56]. More studies are needed to examine the relationships of KD and glucocorticoid use in the setting of SE/RSE.
16. KD and Supplements
Question: What Supplements may Be Warranted when Starting a Ketogenic Diet?
The KD’s inherent shift into fatty acid beta-oxidation predisposes to metabolic acidosis, which can be further compounded if individuals are fasting to achieve ketosis [36]. For these reasons, adequate bicarbonate levels (commonly >17 mmol/L) [7] should be ensured with concomitant sodium bicarbonate [5] and/or potassium citrate supplementation [7].
Beta-oxidation in the mitochondria is reliant on the adequate transport of long-chain fatty acids across the mitochondrial membrane via carnitine [36,53]. Carnitine supplementation is recommended when levels are low (<30 μmol/L) or if the patient is symptomatic, defined by lethargy, weakness and GI symptoms, which are often difficult to assess in a comatose patient [7,36,53]. Carnitine supplementation remains controversial, as levels poorly correlate with tissue stores and symptoms of carnitine deficiency may be difficult to identify in comatose patients [53].
Lastly, it is recommended that a low carbohydrate multivitamin, calcium carbonate and Vitamin D be added [34,36] via nasogastric/gastric tube (NG/G-tube). Most commercially available ketogenic formulas have the recommended daily allowance of these substances. Children with epilepsy have hypovitaminosis D (50%) and are at risk for osteoporosis [36,53]. Phosphorous, [53] administered separately to avoid calcium chelation, is a recommended supplement for its role in bone homeostasis. Lastly, it is our recommendation to supplement either lite salt or table salt for patients that have hyponatremia despite administration of sodium containing intravenous fluids.
17. Termination of Ketotic Therapy
Question: Once Anesthetics Have Been Weaned and/or Seizure Activity Has Improved, How Should KD Be Weaned?
Reasons for diet discontinuation include lack of response, development of complications and need for optimization of nutritional status. There are no clear guidelines to define a clear response to KD, as diseases and patient populations are very heterogeneous, and a clear absolute seizure cessation effect may not be seen. In some cases, allowing for anesthetic wean or antiseizure regimen simplification may be considered successful results. It is our recommendation that before considering therapeutic failure, higher ketotic levels should be pursued if the patient is able to tolerate a more aggressive titration of the KD, as patients, such as our patient, may respond to higher beta-hydroxybutyrate levels.
Like any antiseizure therapy, it is generally recommended to wean the KD diet gradually due to the historical thought that abrupt withdrawal of ketosis can precipitate recurrence of seizures or SE. Abrupt withdrawal of KD is recommended for emergencies only. Thus, gradually reducing the ratio of grams of fats:protein + carbohydrates is recommended (i.e., 4:1 to 3:1 to 2:1) [36]. Despite there being a common notion that overzealous weaning of KD can precipitate previously suppressed seizure activity, a study of over 183 children showed no significant difference in the incidence of seizures worsening between discontinuation/weaning rates (i.e., <1 week vs. 1–6 weeks vs. >6 weeks) [57]. However, there was an increase in seizure activity with faster weaning schedules among a particular cohort: children who had higher percentage (55–90%) of seizure reduction while on the KD. Additionally, among children who successfully stopped KD after seizure cessation, 42% of them were unable to achieve symptom improvement with either ASD or reinitiating of KD upon seizure relapse [58].
We recommend that the clinician use the KD’s treatment success as well as clinical judgement in adopting an individualized weaning schedule. Beginning on HD 194, our patient was weaned from the KD over five days by decreasing the ketogenic formula by 20% every 24 h and replacing it with a traditional critical care formula. Supplemental MCT oil was decreased at the beginning of the weaning process. No complications arose during this transition. Once able to tolerate oral nutrition, the patient will have the autonomy to determine whether to continue KD and contingency plans, such as offering a less strict KD therapy (modified Atkins diet, modified KD), which may be a reasonable alternative.
18. Anticipating and Managing Complications
Question: What Are Some Potential Complications of KD?
Complications of KD are not uncommon and may result in discontinuation of the diet. In the pediatric literature, 30 [6] to 38% discontinuation rates [59] are described due to inability to tolerate the diet or due to complications. These complications include metabolic derangements like dyslipidemia and hyperuricemia, gastrointestinal symptoms, renal stones, osteopenia and cardiac problems like QT prolongation and cardiomyopathy [36,59]. An uncommon yet reported complication is protein-losing enteropathy [60], and while this can be corrected for by cessation of KD, the likely consequence is an increase in seizures. Like osteoporosis and Vitamin D alterations, which may not be relevant in the setting of acute KD administration for RSE, these complications are less relevant in the setting of short-term KD. Rather, more relevant complications to be aware of include dehydration, hyponatremia, metabolic acidosis, hypoglycemia, gastroparesis and nausea/vomiting [5,59].
Aside from poor wound healing and critical illness myopathy, our NORSE patient tolerated KD well and was discharged after 218 days in the hospital. Additional longitudinal studies are needed to examine long-term sequelae of a high fat diet in the context of adults with SE. Future research may focus on complication rates specifically associated with acute administration of KD for adult patients with RSE/SRSE in the neurological ICU setting, as well as cessation upon symptom improvement. Our patient’s neurological examination at discharge was significant for spontaneous eye opening, orientated x 2, minimally talkative with soft but clear speech. She was able to follow simple commands like closing her eyes and wiggle her toes. Strength was 3/5 proximal upper extremity with 2/5 in distal upper and proximal lower extremity. The patient was readmitted three weeks later for cardiac arrest, with subsequent reemergence of status epilepticus. Despite EEG improvement on restarting KD, the patient was eventually transitioned to comfort measures only.
19. Future of KD in Adult SE/RSE/SRSE/NORSE
While the utility of KD in adult populations is certainly promising for the management of RSE and SRSE, there remain several gaps, including a lack of standardized treatment approach, lack of randomized, double-blind controlled studies and hidden carbohydrate sources, which may impair production of ketone bodies. These inconspicuous carbohydrates are found in commonly administered medications for SE including benzodiazepines, antibiotics, electrolyte repletion formulations and even solutions used for oral care. This review offers a brief outline of treatment strategies for KD use in adults and a systematic approach for successfully achieving, maintaining and eliminating ketosis.
Acknowledgments
Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
Conceptualization, C.B.M., J.B.K., K.O.; Methodology, C.B.M., J.B.K., K.O.; Data Curation, C.B.M., M.C.C., L.J.H., K.O.; Writing—Original Draft Preparation, J.B.K..; Writing—Review & Editing, I.N., R.B., N.A.D., E.J.G., C.B.M.; Visualization, J.B.K., C.B.M., Supervision, C.B.M.; Project Administration, C.B.M.; Software, NA; Validation, NA; Formal analysis, NA; Investigation, NA; Resources, NA; Funding, NA. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
This report is a case study, therefore not meeting the Common Rule definition of research as it is not designed to develop generalizable knowledge and did not required ethical approval.
Informed Consent Statement
Given the retrospective nature of this report, the fatal outcome, and the lack of identifiable information, family was not contacted to obtain informed consent.
Conflicts of Interest
The authors declare no conflict of interest. Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
Appendix A
Briviact (brivaracetam injection) [package insert]. Smyrna, G. and I.R.M. UCB.
Cerebyx (fosphenytoin sodium injection) [package insert]. New York, N. and I.R.F. Pfizer.
Propofol injectable emulsion [package insert]. Lake Forest, I. and I.R.M. Hospira.
Ketalar (ketamine hydrochloride injection) [package Insert]. Chestnut Ridge, N., P. Pharmaceutical, and R.A. 2020.
Vimpat (lacosamide injection) [package insert]. Smyrna, G. and I.R.N. UCB.
Midazolam hydrochloride injection [package insert]. Lake Forest, I. and I.R. Hospira.
Thiopental sodium injection [package insert]. Galashiels, U. and L.R.O. Kyowa Kirin.
Valproate sodium injection [package insert]. Eatontown, N. and W.-W.P.C.R.M. 2019.
Sulfamethoxazole and trimethoprim injection [package insert]. Morgantown, W. and M.I.L.R.D. 2020.
Vancomycin hydrochloride for injection [package insert]. Rockford, I. and M.I.L.R.J. 2018.
Carbatrol (carbamazepine extended-release tablet) [package insert]. Lexington, M. and I.R.N. Takeda Pharmaceuticals America.
Levetiracetam immediate-release tablet [package insert]. Chestnut Ridge, N. and P.P.R.S. 2020.
Metamucil (psyllium husk powder) [product information]. Cincinnati, O. and P.G.R.D. 2019.
Divalproex sodium extended-release tablets [package insert]. Bridgewater, N. and A.P.L.R.A. 2020.
Peridex (chlorhexidine gluconate 0.12%) [package insert]. 3M Canada Company Dental Products. 2007.
Figure 1 Drug Interference with achievement of ketosis. Seizure Activity: On HD 14–16, seizure burden was 90% nonconvulsive status epilepticus (NCSE) and decreased to 10–15% by hospital day (HD) 23–24. From HD 30–39, % ictal ranged from 5–20% with HD 40 showing <1% ictal. % Ictal increased briefly during HD 41–47 with an average of 15% ictal but decreased to <1% by HD 48/49. % Ictal remained in the 10–20% range until HD 57 with % ictal < 1. From HD 58–72 % ictal ranged from 5–20% until % ictal <5 by HD 72.
jcm-10-00881-t001_Table 1Table 1 Summary work-up for New-Onset Refractory Status Epilepticus (NORSE) patient.
Categories Serum CSF Imaging Pathology
Infectious: Influenza A/B, H1N1, RPR, HIV, cat scratch panel, tick borne panel, Mycoplasma pneumonia, B Henselae, B quintana (all negative) West Nile Virus, Enterovirus, Bacterial culture, HSV, VZV, Lyme disease, fungal culture, HHV6, EBV, Mycoplasma pneumoniae (all negative)
Inflammatory: ANA, dsDNA, SSA, SSB, SCL 70, CRP, ESR, TPO antibody, thyroglobulin antibody, complements (C3, C4, CH50), ANCA, B2 glycoprotein, anticardiolipin, Antiribosomal P protein Ab, ACE, smooth muscle antibody, skeletal muscle antibody AMPA-R Ab, CASPR2 Ab, DPPX Ab, GABA-B-R Ab, GAD 65, GFAP, LGI1-IgG, mGluR1 Ab, NMDA R Ab
Paraneoplastic: GAD 65, NMDA, voltage gated potassium channel antibody, flow cytometry AChR ganglionic neuronal Ab, Amphiphysin Ab, Antiglial nuclear Ab, Antineuronal nuclear Ab, CRMP-5, Neuronal (V-G) K+ channel Ab, N-Type Calcium channel ab, P/Q type calcium channel Ab, Purkinje cell cytoplasmic Ab, Striational Ab (all negative)
Metabolic: TSH (0.22), Free T4 (1.7 ng/dL), Ammonia (47, 33, 37 µL/dL), serum and urine toxicology (negative)
MRI brain w/wo contrast: restricted diffusion and hyperintense FLAIR signal in the bilateral hippocampi Benign ovarian cyst
CT Chest/abdomen/pelvis: no evidence of ovarian teratoma or other malignancy No malignant cells in CSF
US pelvis: tiny 3–4 mm echogenic focus on the left ovary which may represent a small calcification, however, a tiny teratoma cannot be excluded
MRI pelvis: no evidence of ovarian teratoma
Work-up recommendations from Table 1 from Sculier C, Gaspard N. New onset refractory status epilepticus (NORSE). Seizure. 2019 May; 68:72–78. doi: 10.1016/j.seizure.2018.09.018. Epub 2018 Sep 29. PMID: 30482654. [18]. Influenza A/B: negative; H1N1: negative; Smooth and skeletal muscle antibody: negative; RPR: rapid plasma reagent—negative; ANA: antinuclear antibody—1:2560 titer; dsDNA: double-strand DNA—positive, 38.4 IU/mL; SSA: Sjögren’s Syndrome A—greater than 8; SSB: Sjögren’s Syndrome B—negative; SCL 70: Scleroderma (antitopoisomerase)—negative; Antiribosomal P protein—negative; CRP: C-reactive protein—54 mg/L; ESR: erythrocyte sedimentation rate—51 mm/h; C3/C4/CH50: within normal limits; B2 glycoprotein—negative; Anticardiolipin—negative; TPO: thyroperoxidase antibody—negative; thyroglobulin antibody—negative; ANCA: antineutrophil cytoplasmic antibody—negative; ACE: angiotensin converting enzyme—within normal limits; GAD 65: Glutamic acid decarboxylase—negative; NMDA: N-methyl-D-Aspartate receptor antibody—negative; AMPA: α-amino-3-hydroxy-5-methyl-4 -isoxazolepropionic acid receptor- antibody negative; TSH: thyroid stimulating hormone—within normal limits; HIV: Human immunodeficiency virus—negative; Lyme disease—negative; West Nile Virus—negative; Enterovirus- negative; Bacterial and fungal culture—negative; HSV: Herpes Simplex Virus—negative; VZV: Varicella Zoster Virus—negative; HHV6: Human Herpes Virus 6—negative; EBV: Epstein Barr Virus—negative; GFAP: Glial Fibrillary Acidic Protein—negative; LGI1: Leucine-rich glioma-inactivated—negative; CASPR2: Contactin-associated protein-like 2—negative; DPPX: dipeptidyl-peptidase-like protein 6—negative; GABA: gamma-aminobutyric acid—negative; mGlu1: metabotropic glutamate receptor 1—negative; CRMP-5: CV2/collapsin response mediator protein—negative; Voltage gated potassium channel—negative.
jcm-10-00881-t002_Table 2Table 2 Common antiseizure medications, medications utilized in hospitalized patients and associated carbohydrate, fat, and alcohol content.
Intravenous Product (General Product Concentration)
Carbohydrate Excipient and Amount Per Vial
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Brivaracetam (10 mg/mL) – – – –
Diazepam (5 mg/mL) [41] Propylene glycol: 414 mg 828 mg CHO/10 mg – 79 mg
Famotidine (10 mg/mL) [41] Mannitol: 20 mg 40 mg CHO/40 mg – –
Fosphenytoin [42] – – – –
Lorazepam (2 mg/mL) [42] Propylene glycol: 753 mg – – –
Pentobarbital (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Phenobarbital (130 mg/mL) [41] Propylene glycol: 702 mg – – 79 mg
Phenytoin (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Propofol (10 mg/mL) [41] Glycerol: 22.5 mg/mL 450 mg CHO/h
(20 mL/h) Soybean oil: 100 mg/mL Benzyl alcohol *
Egg Lecithin: 12 mg/mL
Lipid: 100 mg/mL
(1.1 kcal/mL)
Ketamine (multiple) – – – –
Lacosamide (multiple) – – – –
Midazolam (multiple) – – – Benzyl alcohol †
Thiopental (25 mg/mL) – – – –
Valproate (20 mg/mL) – – – –
Trimethoprim-sulfamethoxazole (Bactrim®) diluted in Dextrose 5% W 100 mL per 80–400 mg TMP-SMX Dextrose: 5 g/100 ml Up to 20 g CHO per dose – –
Vancomycin (Vancocin®) diluted in Dextrose 5% W per 1 g/250 mL solution Dextrose: 5 g/100 ml Up to 2 g CHO per dose – –
Enteral Product § (General Product Strength)
Carbohydrate Excipient and Amount Per Unit
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Carbamazepine (extended-release tablet) Lactose monohydrate ‡
Microcrystalline cellulose ‡ – – –
Clobazam (10 mg tablet) [43] 105.3 mg/tablet ≈100 mg/10 mg – –
Clonazepam (0.5 mg tablet) [43] 143.5 mg/tablet ≈2800 mg/10 mg – –
Levetiracetam (immediate release tablet) Croscarmellose sodium ‡
Polyethylene glycol 3350 ‡
Polyethylene glycol 6000 ‡ – – Polyvinyl alcohol
Psyllium (Metamucil) packet 9 g CHO/tablespoon 27 g CHO/day (TID) – –
Divalproex sodium (extended-release tablet) Hypromelloses ‡
Lactose monohydrate ‡
Polyethylene glycol ‡
Propylene glycol ‡
Macrogol ‡
Microcrystalline cellulose ‡ – – n-Butyl alcohol
Isopropyl alcohol
Polyvinyl alcohol
See Appendix A for package inserts. * Present at 1.5 mg/mL in all vial sizes (0.15% w/v). Avoid use in pediatric populations due to benzyl alcohol content. † Present at 10 mg/mL in all vial sizes (1% w/v), except preservative-free formulations. Avoid use in pediatric populations due to benzyl alcohol content. ‡ Unknown amount of relative excipient may affect ketosis but is likely clinically insignificant. § Solution and suspension formulations should be avoided if possible as they usually contain sugars that will affect ketosis.
jcm-10-00881-t003_Table 3Table 3 Ketogenic Diet checklist for Status Epilepticus.
Pearls to Consider for Starting and Maintaining a Ketogenic Diet (KD)
I. KD initiation
○ Check fasting lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D serum levels
○ Record baseline weight and height
○ Continuous video EEG
○ Dietitian/nutrition consult (consider pediatric nutritionist)
○ Stop current enteral formula
○ Reduce carbohydrate content in medications and parenteral fluids with pharmacy input
○ Active communication with nursing/pharmacy, EMR warnings, and signs in room are crucial to avoid medication/IV-containing carbohydrates
○ Begin KD (e.g., KetoCal/MCT oil)
○ Include multivitamin injection, Vit. D and calcium supplementation via nasogastric tube/gastric tube
○ Change any oral agents from liquid formulation to crushed tablet formulation
II. KD maintenance
○ Remove all common carbohydrate excipients in intravenous fluids, including:
○ Glycerin
○ Maltodextrin
○ Propylene glycol
○ Sugars (dextrose, fructose, glucose, lactose, sucrose, corn syrup)
○ Sugar alcohols (glycerol, mannitol, sorbitol)
○ Starches
○
KD can be challenged via coadministration of other meds & IVs!
III. Pitfalls to consider:
○ Contraindications: unstable metabolic derangements, hemodynamic instability, coagulopathy/bleeding diathesis, pancreatitis, liver failure, severe hyperlipidemia, ileus, pregnancy, known fatty acid oxidation disorder or pyruvate carboxylase deficiency
○
Propofol infusions cannot be given within 24 h before starting a KD!
Adapted & modified from Table 3 from Thakur KT, Probasco JC, Hocker SE, et al. Neurology. 2014 Feb 25; 82(8): 665–670. [4]. | ACYCLOVIR, LEVETIRACETAM, LORAZEPAM, PENTOBARBITAL, PHENYTOIN, PROPOFOL, VALPROIC ACID | DrugsGivenReaction | CC BY | 33671485 | 19,466,490 | 2021-02-22 |
What was the administration route of drug 'LORAZEPAM'? | Pearls and Pitfalls of Introducing Ketogenic Diet in Adult Status Epilepticus: A Practical Guide for the Intensivist.
Background: Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of a ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and effective. Methods: We describe our experience, including the challenges of achieving and maintaining ketosis, in an adult with new onset refractory status epilepticus (NORSE). Case Vignette: A previously healthy 29-year-old woman was admitted with cryptogenic NORSE following a febrile illness; course was complicated by prolonged super-refractory SE. A comprehensive work-up was notable only for mild cerebral spinal fluid (CSF) pleocytosis, elevated nonspecific serum inflammatory markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI). Repeat CSF testing was normal and serial MRIs demonstrated resolution of edema and diffusion restriction with progressive hippocampal and diffuse atrophy. She required prolonged therapeutic coma with high anesthetic infusion rates, 16 antiseizure drug (ASD) trials, empiric immunosuppression and partial bilateral oophorectomy. Enteral ketogenic formula was started on hospital day 28. However, sustained beta-hydroxybutyrate levels >2 mmol/L were only achieved 37 days later following a comprehensive adjustment of the care plan. KD was challenging to maintain in the intensive care unit (ICU) and was discontinued due to poor nutritional state and pressure ulcers. KD was restarted again in a non-ICU unit facilitating ASD tapering without re-emergence of SE. Discussion: There are inconspicuous carbohydrates in commonly administered medications for SE including antibiotics, electrolyte repletion formulations, different preparations of the same drug (i.e., parenteral, tablet, or suspension) and even solutions used for oral care-all challenging the use of KD in the hospitalized patient. Tailoring comprehensive care and awareness of possible complications of KD are important for the successful implementation and maintenance of ketosis.
1. Introduction
Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and potentially effective [1,2,3,4,5]. Most often used in childhood epilepsies, KD has emerged as a potential adjunctive treatment for pediatric SE [6,7]. We describe our experience with an adult with new onset refractory status epilepticus (NORSE) focusing on the unexpected challenge of achieving and maintaining ketosis. Practical advice, and a comprehensive review of factors potentially jeopardizing ketosis commonly encountered in the critical care setting and alternatives are provided.
2. Presentation
A previously healthy 29-year-old woman was admitted to another institution with new onset refractory status epilepticus (NORSE) following a febrile illness with a course complicated by prolonged super-refractory SE. Three days prior to presentation she developed fever, headache, emesis and fatigue in the setting of being in contact with her child with an upper respiratory tract infection. On the morning of admission, her friend attempted to awaken her for work and found her unresponsive and convulsing. In the emergency department, she was lethargic and mumbling incoherently. During her initial evaluation she had a witnessed 45-s bilateral tonic-clonic seizure that was aborted with 2 mg lorazepam intravenously. Head computed tomography was unremarkable and initial cerebrospinal fluid (CSF) analysis showed a mononuclear pleocytosis (2 RBC, 41 nucleated cells (57% mononuclear cells), glucose 93, protein 54)). A one-hour electroencephalogram (EEG) showed diffuse delta activity admixed with sleep spindles and K complexes without epileptiform discharges. She was monitored in the step-down unit and treated with levetiracetam and acyclovir. On hospital day two, she was somnolent but arousable to voice; she was able to follow simple midline commands, state her name and the current president, but was disoriented to time. She was noted to have twitching of her face, but no EEG was done at that time. By hospital day three, she began experiencing brief convulsive seizures which were aborted with intravenous lorazepam and always associated with recovery of consciousness. At that point, phenytoin (1 g loading dose, maintenance at 100 mg q8h) was added to her antiseizure drug (ASD) regimen. On hospital day four, she had multiple convulsive seizures without return to baseline, complicated by acute hypoxic respiratory failure requiring intubation. She was transferred to the intensive care unit (ICU) where she was started on propofol, and valproic acid (20 mg/kg loading dose, maintenance at 750 mg Q8H) was added. Routine EEG captured multiple discrete right frontal and centrotemporal onset seizures correlating with episodes of face twitching. She was started on pentobarbital infusion (5 mg/kg bolus, maintenance at 1 mg/kg per hour) and transferred to our center for continuous EEG monitoring.
3. Question: How Is Prolonged Seizure Activity Classified and What Are Potential Etiologies to Be Considered?
According to the most recent classification set by The International League Against Epilepsy, SE is a “condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures” [8]. While operational SE definitions based on time-domains vary according to seizure type, it is generally accepted that convulsive seizure activity lasting either greater than 5 min continuously, or two or more seizures during which the individual does not recover to baseline between seizures, represents SE [8]. Inhibitory gamma-aminobutyric acid (GABA) neurons located in the pars reticulata of the substantia nigra are key in seizure termination [9]. During status epilepticus, marked alteration of GABA metabolism occurs in this region and results in disinhibition of excitatory pathways: GABA synthesis slows down [10]. GABA turnover time increases up to three-fold, [10] and GABA receptors (originally located in the surface of the cell membrane) migrate to the intracellular space within minutes of ongoing seizure activity [11,12,13]. Prompt initiation of abortive therapies is key, as the internalization of GABA receptors contributes to refractoriness to treatment.
Emergent administration of parenteral benzodiazepine (e.g., up to 0.1 mg/kg of lorazepam) is considered the first-line therapy for SE [14]. If a patient fails to respond to a benzodiazepine and a second appropriately selected and dosed ASD at adequate doses, they are in refractory status epilepticus (RSE). It has been reported that one in five RSE patients go on to develop super-refractory status epilepticus (SRSE), defined as (1) ongoing seizures lasting 24 h or more after onset of anesthetic therapy (i.e., propofol) or (2) recurrence of SE upon reduction or withdrawal of therapeutic anesthetic coma [15]. The clinical presentation of RSE in patients without overt acute or remote brain injury, prior epilepsy, or acute toxic/metabolic explanation is consistent with New Onset Refractory Status Epilepticus—NORSE [16]. Febrile Infection-Related Epilepsy Syndrome (FIRES) is a subset of NORSE, in which a febrile infectious illness precedes SE onset by 1–14 days [14,15,16]. Thus, our patient qualified as having the syndrome of FIRES as well as NORSE. Further, clinical criteria for unequivocal electroencephalographic status epilepticus in patients without known epileptic encephalopathy has been established in the Salzburg consensus: (1) repeating epileptiform discharges occurring >2.5 Hz, or (2) repeating epileptiform discharges occurring ≤2.5 Hz or rhythmic delta/theta activity >0.5 Hz plus (a) electroclinical response (improvement) following intravenous ASD challenge, (b) subtle clinical correlate associated with pattern, or (c) typical temporal and spatial evolution of pattern [17].
Determining the underlying etiology of SE may seem a daunting task. However, its importance in achieving seizure cessation cannot be underestimated. Outcome following SE is dependent on the etiology of seizures. Further, appropriately recognizing the electroclinical classification of seizures (i.e., identifying the seizure semiology and its electrographic signature) may not only help selection of therapy but also identify potential etiologies [8]. Among NORSE patients, an etiology is found in up to 50% of cases [16]. Of those with an identifiable cause, the majority (37%) had an autoimmune cause (both nonparaneoplatic and paraneoplastic), while 8% had a probable infectious cause [16]. Thus, if an autoimmune etiology is diagnosed or clinically suspected, immune modulating therapies such as high-dose corticosteroids, intravenous immunoglobulin (IVIg) or plasma exchange therapy, followed by monoclonal antibodies and/or interleukin inhibitors, should be considered early in the course.
Our patient underwent a comprehensive work-up to determine the etiology of NORSE, as summarized on Table 1, which was notable only for mild CSF pleocytosis, elevated nonspecific inflammatory serum markers and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI).
4. Question: What Are the Initial Steps in the Therapeutic Algorithm for Status Epilepticus?
Benzodiazepines are the first-line treatment for SE [14,19] with slower-acting, less sedating parenteral ASDs being the second line (e.g., phenytoin, fosphenytoin, valproate and levetiracetam; and possibly lacosamide and phenobarbital). The Established Status Epilepticus Treatment Trial (ESETT) found no difference in efficacy between fosphenytoin (20 mgPE/kg), valproate (40 mg/kg) and levetiracetam (60 mg/kg) in children, adults and older adults; these ASDs were able to abort SE within an hour in nearly 50% of patients [20]. Once the second-line, or a combination of medications, fails to result in seizure cessation, continuous intravenous infusions of anesthetics (i.e., midazolam, pentobarbital, propofol, ketamine) are often recommended [14,19].
In patients with SE, anesthetic use is associated with longer hospital stay, but not in-hospital or 90-day mortality [21]. Amongst NORSE patients who receive anesthetics, the mortality is high. However, the use of anesthetics is not associated with poor outcome [16]. In 61 patients with RSE, those who underwent deep sedation (defined as either EEG showing burst suppression or isoelectric activity) had both poorer long-term prognosis and increased mortality [22]. Burst suppression on EEG is defined as intermittent alternating periods of low amplitudes (<10 uV for burst suppression; 10–20 uV for burst attenuation) interrupting a background, which may consist of waves of varying frequencies. Earlier attainment of burst suppression may allow for a more rapid anesthetic wean [23], and it is important to frequently monitor the EEG and titrate anesthetic dose as appropriate. The goal of anesthetic use in RSE is the resolution of epileptiform activity in order to avoid physiologic effects while the underlying cause is identified and treated [24,25].
In our case, 16 antiseizure drug trials in various combinations and high anesthetic infusion rates were attempted. RSE persisted despite 160 mg/h (2.5 mg/kg/h) of midazolam prompting the initiation of ketamine. Despite improved seizure burden following ketamine bolus (1.5 mg/kg), reemergence of SE occurred despite up-titration of ketamine to our maximum infusion rate (7.5 mg/kg/h). Her EEG responded to propofol and pentobarbital with long periods of suppression, although her background remained with abundant generalized periodic discharges (GPD) at 2.5–3 Hz, qualifying as ongoing electrographic SE. [17,26] Burst suppression was eventually achieved with pentobarbital at 3 mg/kg/h and propofol at 40 mcg/kg/min. However, due to re-emergence of 2 Hz GPDs along with breakthrough seizures on attempted wean, she remained in a medically induced coma for over three months.
5. Question: What Are Potential Rescue Therapeutic Approaches to the Management of Super-Refractory Status Epilepticus?
Refractory and super-refractory SE and their complications are associated with significant morbidity including death, neuronal damage and systemic complications like cardiomyopathy, ischemic bowel, pulmonary edema and renal failure [27]. This highlights the necessity for a prompt and aggressive treatment approach. In the setting of treatment failure, alternative treatment options include inhaled anesthetics, magnesium infusion, pyridoxine, hypothermia, electrical and magnetic stimulation, additional immunotherapy, enteral ASDs and the KD [28].
Given a high suspicion for an autoimmune process, our patient was treated with intravenous methylprednisolone (1 g daily for 5 days), IVIg, plasma exchange and cyclophosphamide. Serial MRIs demonstrated resolution of edema and diffusion restriction with gradually progressive atrophy, predominantly in the hippocampi, and repeat CSF analysis was normal. She underwent empiric bilateral partial oophorectomy for an echogenic focus in her left ovary and concern for possible occult microteratoma, possibly secondary to N-methyl-D-Aspartate (NMDA) encephalitis (NMDA CSF < 1:1 and serum < 1:10) [29].
6. Ketogenic Diet
Ketosis is commonly defined as sustained beta-hydroxybutyrate levels > 2 mmol/L [30] or a urinary acetoacetate level of >40 mg/dL [31]. There is evidence supporting the use of KD in children with autoimmune epilepsies, symptomatic epilepsy syndromes, pediatric refractory and super-refractory SE [6,32]. In a study of 10 children (age six months—16 years old) with refractory focal SE, initiation of a KD resulted in lower seizure burden (50% reduction in seizures for 70% of the cohort) and resolution of seizures in 20% [6]. In the minority of patients with less than 50% seizure reduction (n = 3), severe adverse events (pancreatitis or severe vomiting and hypoglycemia) prompted KD discontinuation. In another study of 12 children with fever induced refractory epileptic encephalopathy, KD was able to stop seizures within two days following ketonuria [32]. Nevertheless, the side effects of KD limit its widespread use, and successful ketosis must be attained for seizure control.
More recently, KD has been evaluated in adult patients; a systematic review of 38 adult patients with RSE or SRSE demonstrated that 82% were able to achieve SE cessation with KD [33]. There are several complex mechanisms for the efficacious effect of KD on reducing seizure activity, which result from reduction in glucose intake, ketone body production and alteration of the gut microbiome. The metabolic changes induced by KD alter the balance of excitatory and inhibitory neurotransmitters, lead to reductions in oxidative stress and systemic as well as neuroinflammation, and have further long-term effects on gene expression [3,34].
We sought KD as a rescue therapy after conventional treatments had failed.
7. Question: What Are Some Factors Should the Clinician Consider When Selecting and Initiating KD for Adults with SE?
Initiating KD Safely
Determining the optimal patient for whom to implement KD requires a comprehensive evaluation of the patient’s past medical history, comorbidities and current clinical status. As with all treatment strategies, particularly in the ICU setting, a thoughtful risk-benefit analysis is warranted. Inborn errors of metabolism are a contraindication to KD [35,36]. However, these conditions most often present in early childhood, and rarely in adults, so screening is not routinely obtained prior to KD initiation in adults [1,2]. Other contraindications of KD include unstable metabolic (mitochondrial enzyme deficiencies) conditions, liver failure, acute pancreatitis, pregnancy and an inability to tolerate enteral feeds [5]. Protocols typically avoid starting KD within 24 h of propofol infusions to avoid possibly fatal propofol infusion syndrome, characterized by metabolic acidosis, lipemia, rhabdomyolysis and myocardial failure [37].
8. Question: Should You Fast the Patient to Achieve Ketosis Quickly? If So, How Long and What Are Potential Consequences? If You Decide Not to Fast, Can Ketosis Still Be Achieved?
Variations in KD Protocols
Historically, KD implementation in the setting of childhood epilepsy included an initial fasting period ranging anywhere from 12 [7] to 48 [36,38] hours or more. Once satisfactory ketosis is achieved, ketogenic formulations or meals (typically 4:1 g of fat: carbohydrate + protein ratio) can then be titrated as tolerated until full caloric requirements are met. To avoid potential complications of a fasting period (e.g., dehydration, hypoglycemia), Kim et al. began KD without initial fasting and found equivalency in time to ketosis and seizure reduction in 41 children with intractable epilepsy compared to a retrospective control population of 83 children who fasted prior to KD initiation [39]. While rates of hypoglycemia were similar when compared to controls, there were reduced rates of dehydration and reduced length of hospital stay.
An alternative, yet equally efficacious approach for childhood epilepsy, does not involve initial fasting or limiting caloric intake. This protocol differs from others in the fact that there is a gradual increase from 1:1 to 2:1 until the goal 4:1 ratio is reached [38]. This gradual induction and establishment of ketosis in children diagnosed with intractable epilepsy showed an equal reduction in seizure activity yet decreased weight loss and episodes of hypoglycemia, acidosis and dehydration. Nevertheless, since time is a major factor in terms of avoiding neurologic and systemic consequences of SE, a more aggressive approach to KD initiation (i.e., fasting and/or more rapidly advancing to full calories as tolerated) may be warranted in this setting.
Individual patient characteristics including age, illness severity, duration of anesthetic use prior to diet initiation resulting in reduction in gastrointestinal motility, and diet complications, may not allow the luxury of initiating a preferred protocol with certain ketogenic ratio or at a faster rate. This was evident in Cobo’s pediatric SRSE study in which ratios were started as low as 0.75:1 in some instances, and ratios never exceeding 2:1 in some cases [7]. The need for higher protein intake (often in cases of poor wound healing, malnutrition and/or low basal resting energy expenditure) challenges the use of higher fat:protein + carbohydrate ratios, although this is more of a concern with chronic KD use rather than in the acute setting of RSE and SRSE. A possible way to maximize ketosis when using lower ratios (thus, higher protein intake) is the addition of medium-chain triglyceride oils as they yield greater amounts of ketones/kcal of energy than longer chain varieties [36].
We used these principles, most frequently used in the setting of childhood epilepsy, to initiate KD for our NORSE patient with the goal of achieving ketosis quickly. Our patient was initially started on KD on hospital day 28 (HD 28) with a goal of 5:1 ratio (KetoCal® 4:1 at 55 mL/h plus 33 mL medium-chain triglycerides (MCT) oil to balance carbohydrate intake from medications, documented as 51 g daily on HD 30). At this time, supplemental protein via PROsource® was discontinued to assist with achieving ketosis. On HD 35, beta-hydroxybutyrate (BHB) levels continued to show inadequate ketosis [Figure 1] prompting the increase to 6:1 with additional MCT Oil. Through HD 65, beta-hydroxybutyrate continued to fluctuate below the 2.0 goal. On HD 71, beta-hydroxybutyrate again dropped with the only documented potential carbohydrate source (at that time) being a milk and molasses enema administered by a care team to alleviate constipation. The decision was made to return to a higher carbohydrate-containing formula and refocus nutrition goals on wound healing. At this time, our patient was identified as meeting the criteria for severe malnutrition based on weight loss of >7.5% in three months and limited energy intake for greater than or equal to five days [40].
9. Question: What Factors Can Impede the Success of Achieving Ketosis, and thus Jeopardize the Utility of KD?
Despite initiating KD with complete enteral feeds on hospital day 28, our patient was only able to reach ketosis a significant 37 days later (Figure 1). After a comprehensive assessment of the care plan, the culprit was found: inconspicuous carbohydrate-containing medications, infusions and oral-care solutions routinely given in the setting of a neurological ICU (Table 2).
10. Hidden Carbohydrates Can Hinder Achievement of Ketosis
In our experience, the most likely medication-induced barriers to ketosis include sedatives, antiseizure drugs and antibiotics. Benzodiazepines are not created equally when it comes to hidden/nonobvious carbohydrate content. Diazepam (Valium® 5 mg/mL) and Lorazepam (Ativan® 2 mg/mL) have been shown to have 40% and 80% propylene glycol content, respectively, which equates to an overall carbohydrate content of 0.4 g/mL and 0.8 g/mL [42]. Intake of this carbohydrate content in patients with status epilepticus on KD may hinder achieving ketosis, but can also precipitate propylene glycol toxicity and associated anion-gap, metabolic acidosis [44].
While the carbohydrate load of each individual dose may be inconsequential, the cumulative dose given to patients in extended hospital stays may be significant. For example, initial administrations of injectable lorazepam, 2 mg every 6 h yields approximately 3 g of carbohydrate per day [44]. For context, this patient’s energy assessment used an ideal body weight of 64.5 kg, with daily caloric requirements calculated to total 2260 kcal/day (35 kcal/kg). Using KD at a 4:1 ratio (a common target for KD), the macronutrient breakdown is 226 g fat, 51.6 g protein, and 4.9 g carbohydrates. Thus, lorazepam would have contributed over half of the allotted daily carbohydrate load. Figure 1 shows several instances where lorazepam administration was associated with significant troughs in beta-hydroxybutyrate levels. When benzodiazepine infusions are warranted for refractory cases, our recommendation would be to consider midazolam as an alternative; midazolam does not have propylene glycol in its formulation, resulting in lower rates of anion-gap metabolic acidosis [45]. Regarding enteral administration of benzodiazepines, it is worth noting that clobazam (Onfi ®) and clonazepam (Klonopin®) contain 105 mg and 143.5 mg of carbohydrates (i.e., lactose, starch) per 10 mg/0.5 mg tablet, respectively [Table 2]. When selecting benzodiazepines for treatment of SE in patients treated with KD, it is important to evaluate the carbohydrate content for the selected benzodiazepine and the administration method. Generally, solutions and suspensions should be avoided due to high carbohydrate containing excipients.
Another class of widely used sedatives, often with the potential to inadvertently hinder beta-hydroxybutyrate levels, are the barbiturates, particularly pentobarbital (Nembutal® 50 mg/mL) and phenobarbital (Phenobarb® 130 mg/mL). Barbiturates are commonly used in RSE. However, they have a high propylene glycol content (pentobarbital 414 mg/50 mg vial, phenobarbital 702 mg/130 mg vial [42] amounting to an overall carbohydrate content of 2.9 g/h when pentobarbital is infused at a rate of 5 mg/kg/h for a 70 kg patient) [Table 2]. We suggest that ketamine (and midazolam, as discussed above) be considered as an alternative to pentobarbital in patients with status epilepticus on KD, given their lack of propylene glycol [46], This same concept can be applied for phenytoin (Dilantin® 50 mg/mL), which contains 40% propylene glycol [42] amounting to a carbohydrate content of 414 mg (plus an additional 79 mg of alcohol). These principles can be observed in Figure 1 where beta-hydroxybutyrate levels drop on HD 52, corresponding with a phenobarbital load (a disruption in feeds also occurred to administer phenytoin by mouth). We recommend that fosphenytoin be used instead to avoid propylene glycol excipients (Table 2). Similarly, on HD 56, beta-hydroxybutyrate dropped to 0.63 mmol/L with a medication review showing intravenous phenobarbital administered overnight. Lastly, another note of caution regarding anesthetic infusions: propofol contains 1.1 kcal/mL (mostly from fats), which provides approximately 528 kcal per day (presuming 20 mL/h). While this increased caloric load may aid in ketosis, its 450 mg of glycerol per 20 mL vial may hinder ketosis (Table 2).
11. Noncarbohydrate Related Hindrance of Ketosis
Among children with refractory epilepsy, concomitant lamotrigine use decreases KD’s efficacy in seizure reduction [47]. This may be explained by ketosis increasing the metabolism/inactivation of lamotrigine via glucosyltransferases, which ultimately results in increased glutamate release. Lastly, one must not forget that while medication use can influence KD, the inverse is also true. While most serum concentrations of ASD were not found to significantly change upon KD use, valproic acid levels have been shown to decrease [48]. Therefore, it is recommended to monitor valproic acid while using KD therapy.
12. Question: Aside from Sedative Agents, What Other Widely Used Agents in the Neurological ICU Can Hinder Ketosis?
12.1. Antimicrobials and Respective Diluents as Source of Carbohydrates
Various antibiotics that are used frequently in the neurological ICU [49,50] can hinder ketosis. Intravenous trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim®) requires reconstitution with dextrose 5% water and, similarly, vancomycin is often diluted in dextrose 5% water prior to intravenous administration (Table 2). Figure 1 (line graph) shows several instances in which administration of TMP-SMX and vancomycin were associated with troughs in beta-hydroxybutyrate levels.
12.2. Non “Medications” Contain Hidden Carbohydrates
Hidden carbohydrates are found in oral care solutions such as chlorhexidine, dietary supplements and fiber. Chlorhexidine 0.12% oral solution (PeridexTM), reported to be superior to toothbrushing at reducing early ventilator-associated pneumonia [51], contains glycerin and ethyl alcohol (see Appendix A), both carbohydrate-containing substances that can affect KD [52]. Oral fiber supplements, such as psyllium, have a significant carbohydrate load (e.g., 9 g/tablespoon) (Table 2). However, as fiber has a lower glycemic index compared to other carbohydrate-containing sources in the ICU setting, it may still be used in some instances to counteract constipation.
12.3. Comprehensive Approach to Implementing KD in Adult SE
Adopting a systematic approach is key for the successful implementation and maintenance of a ketotic state. A checklist is provided in Table 3 with a summary of the suggested steps for successful KD initiation [4].
13. Question: What Laboratory Values Should the Intensivist Pay Particular Attention to When Using KD?
Baseline assessment of certain serum (lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D, and free and total carnitine) [41] and anthropometric (weight, height) parameters [5,33,53] are imperative to effectively see how values trend overtime with KD. This objective data collected longitudinally allows monitoring of metabolic and systemic side effects of KD to allow for cessation if need-be.
After deciding that KD is appropriate, the next step is to carefully review all standing orders in the patient’s chart to identify potential sources of hidden carbohydrates and replace with alternatives. Guidance by the dietary/nutrition team as well as an ICU pharmacist are recommended to improve success with achieving and maintaining ketosis. If possible, a nutritionist with knowledge and experience with managing a KD is preferred, which may necessitate involving the pediatric nutrition team.
In the critical care setting, nutrition is often dictated by the critical care team via administration of formula tube feeding, and patient compliance is not a key factor for achieving ketosis. Route of administration does impact ketosis as suspension or elixir medications, [53] the preferred formulations via percutaneous gastrostomies (PEG) or other enteral routes, must be replaced by alternative formulations with lower carbohydrate content [7]. Additionally, dextrose-free diluents [52] must be used whenever able in intravenous drug formulations. Unavoidable carbohydrates can be balanced with a calculated dose of fat in the form of MCT oil or a commercially available emulsified oil (provided that this addition coincides with caloric and macronutrient percentages discussed later). Additionally, this puts the patient at an increased risk for gastrointestinal complications such as steatorrhea, emesis and reflux.
14. Ketosis Maintenance and Surveillance
Inducing ketosis is only the first step in tackling SE. While a ketotic state is commonly defined as beta-hydroxybutyrate >2 mmol/L [30], similarly to antiseizure drugs, some individuals require higher level of ketosis (or antiseizure drugs) to achieve optimal seizure control. Thus, individual thresholds for optimal ketotic state may vary. In the presented case, the best therapeutic effect was noted with beta-hydroxybutyrate >3.5. Maintaining ketosis above a certain therapeutic level proves to be difficult, particularly when higher targets are required such as >3 mmol/L beta-hydroxybutyrate [7]. For example, Cobo’s case series illustrated that children with SRSE can have sudden, unexplained drops in beta-hydroxybutyrate levels.
After KD was stopped on HD 73 due to poor nutritional status, KD was reinitiated on HD 106 as the patient was no longer on bolus medications with high carbohydrate content. Ketosis was achieved rapidly over two days, with a beta-hydroxybutyrate of 2.34 mmol/L target once the goal of 6:1 ratio 18 kcal/kg was reached. The rapid achievement of ketotic state likely resulted from several days of fasting prior to its initiation in the setting of percutaneous gastrostomy placement and enterocutaneous fistula repair. The patient remained in ketosis, with beta-hydroxybutyrate levels fluctuating between 1.93–5.32 mmol/L, during which time seizures were best controlled when beta-hydroxybutyrate levels were >3.5 mmol/L.
Constant evaluation and re-evaluation of patient intake, including intravenous fluids, must be conducted. It is imperative to remove all common exogenous carbohydrates including glycerin, maltodextrin, propylene glycol, dextrose, fructose, glucose, lactose, sucrose, corn syrup, sugar alcohols and starches [52]. Appropriate alternatives include normal saline, balanced crystalloid or lactated Ringer’s solution.
15. Question: What Natural Physiologic Mechanisms Must Be Accounted for When Attempting to Achieve/Maintain Ketosis?
In addition to exogenous carbohydrate management, the intensivist must not overlook endogenous perturbations of glucose homeostasis. Commonly measured anywhere from every four [54] to eight hours after initiation of KD [7], fluctuations are commonly seen in the pediatric population as the clinician attempts to titrate to a glucose target level of 60–79 mg/dL [7]. While the lower limit of 40 mg/dL is referenced in the Academy of Nutrition and Dietetics Practice Paper, the clinicians at Yale New Haven Hospital use a slightly higher limit of 50 mg/dL when evaluating for KD initiation. Ketosis can be threatened by endogenous gluconeogenesis occurring during infection or injury [55]. The topic of glucose perturbations brings up the discussion of whether the use of glucocorticoids concurrently with KD hinders the diet’s efficacy. Among children with epilepsy being treated with KD, there have been reports of glucocorticoid use (even inhaled) being associated with seizure return, elevated glucose and ketosis hindrance [56]. More studies are needed to examine the relationships of KD and glucocorticoid use in the setting of SE/RSE.
16. KD and Supplements
Question: What Supplements may Be Warranted when Starting a Ketogenic Diet?
The KD’s inherent shift into fatty acid beta-oxidation predisposes to metabolic acidosis, which can be further compounded if individuals are fasting to achieve ketosis [36]. For these reasons, adequate bicarbonate levels (commonly >17 mmol/L) [7] should be ensured with concomitant sodium bicarbonate [5] and/or potassium citrate supplementation [7].
Beta-oxidation in the mitochondria is reliant on the adequate transport of long-chain fatty acids across the mitochondrial membrane via carnitine [36,53]. Carnitine supplementation is recommended when levels are low (<30 μmol/L) or if the patient is symptomatic, defined by lethargy, weakness and GI symptoms, which are often difficult to assess in a comatose patient [7,36,53]. Carnitine supplementation remains controversial, as levels poorly correlate with tissue stores and symptoms of carnitine deficiency may be difficult to identify in comatose patients [53].
Lastly, it is recommended that a low carbohydrate multivitamin, calcium carbonate and Vitamin D be added [34,36] via nasogastric/gastric tube (NG/G-tube). Most commercially available ketogenic formulas have the recommended daily allowance of these substances. Children with epilepsy have hypovitaminosis D (50%) and are at risk for osteoporosis [36,53]. Phosphorous, [53] administered separately to avoid calcium chelation, is a recommended supplement for its role in bone homeostasis. Lastly, it is our recommendation to supplement either lite salt or table salt for patients that have hyponatremia despite administration of sodium containing intravenous fluids.
17. Termination of Ketotic Therapy
Question: Once Anesthetics Have Been Weaned and/or Seizure Activity Has Improved, How Should KD Be Weaned?
Reasons for diet discontinuation include lack of response, development of complications and need for optimization of nutritional status. There are no clear guidelines to define a clear response to KD, as diseases and patient populations are very heterogeneous, and a clear absolute seizure cessation effect may not be seen. In some cases, allowing for anesthetic wean or antiseizure regimen simplification may be considered successful results. It is our recommendation that before considering therapeutic failure, higher ketotic levels should be pursued if the patient is able to tolerate a more aggressive titration of the KD, as patients, such as our patient, may respond to higher beta-hydroxybutyrate levels.
Like any antiseizure therapy, it is generally recommended to wean the KD diet gradually due to the historical thought that abrupt withdrawal of ketosis can precipitate recurrence of seizures or SE. Abrupt withdrawal of KD is recommended for emergencies only. Thus, gradually reducing the ratio of grams of fats:protein + carbohydrates is recommended (i.e., 4:1 to 3:1 to 2:1) [36]. Despite there being a common notion that overzealous weaning of KD can precipitate previously suppressed seizure activity, a study of over 183 children showed no significant difference in the incidence of seizures worsening between discontinuation/weaning rates (i.e., <1 week vs. 1–6 weeks vs. >6 weeks) [57]. However, there was an increase in seizure activity with faster weaning schedules among a particular cohort: children who had higher percentage (55–90%) of seizure reduction while on the KD. Additionally, among children who successfully stopped KD after seizure cessation, 42% of them were unable to achieve symptom improvement with either ASD or reinitiating of KD upon seizure relapse [58].
We recommend that the clinician use the KD’s treatment success as well as clinical judgement in adopting an individualized weaning schedule. Beginning on HD 194, our patient was weaned from the KD over five days by decreasing the ketogenic formula by 20% every 24 h and replacing it with a traditional critical care formula. Supplemental MCT oil was decreased at the beginning of the weaning process. No complications arose during this transition. Once able to tolerate oral nutrition, the patient will have the autonomy to determine whether to continue KD and contingency plans, such as offering a less strict KD therapy (modified Atkins diet, modified KD), which may be a reasonable alternative.
18. Anticipating and Managing Complications
Question: What Are Some Potential Complications of KD?
Complications of KD are not uncommon and may result in discontinuation of the diet. In the pediatric literature, 30 [6] to 38% discontinuation rates [59] are described due to inability to tolerate the diet or due to complications. These complications include metabolic derangements like dyslipidemia and hyperuricemia, gastrointestinal symptoms, renal stones, osteopenia and cardiac problems like QT prolongation and cardiomyopathy [36,59]. An uncommon yet reported complication is protein-losing enteropathy [60], and while this can be corrected for by cessation of KD, the likely consequence is an increase in seizures. Like osteoporosis and Vitamin D alterations, which may not be relevant in the setting of acute KD administration for RSE, these complications are less relevant in the setting of short-term KD. Rather, more relevant complications to be aware of include dehydration, hyponatremia, metabolic acidosis, hypoglycemia, gastroparesis and nausea/vomiting [5,59].
Aside from poor wound healing and critical illness myopathy, our NORSE patient tolerated KD well and was discharged after 218 days in the hospital. Additional longitudinal studies are needed to examine long-term sequelae of a high fat diet in the context of adults with SE. Future research may focus on complication rates specifically associated with acute administration of KD for adult patients with RSE/SRSE in the neurological ICU setting, as well as cessation upon symptom improvement. Our patient’s neurological examination at discharge was significant for spontaneous eye opening, orientated x 2, minimally talkative with soft but clear speech. She was able to follow simple commands like closing her eyes and wiggle her toes. Strength was 3/5 proximal upper extremity with 2/5 in distal upper and proximal lower extremity. The patient was readmitted three weeks later for cardiac arrest, with subsequent reemergence of status epilepticus. Despite EEG improvement on restarting KD, the patient was eventually transitioned to comfort measures only.
19. Future of KD in Adult SE/RSE/SRSE/NORSE
While the utility of KD in adult populations is certainly promising for the management of RSE and SRSE, there remain several gaps, including a lack of standardized treatment approach, lack of randomized, double-blind controlled studies and hidden carbohydrate sources, which may impair production of ketone bodies. These inconspicuous carbohydrates are found in commonly administered medications for SE including benzodiazepines, antibiotics, electrolyte repletion formulations and even solutions used for oral care. This review offers a brief outline of treatment strategies for KD use in adults and a systematic approach for successfully achieving, maintaining and eliminating ketosis.
Acknowledgments
Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
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Author Contributions
Conceptualization, C.B.M., J.B.K., K.O.; Methodology, C.B.M., J.B.K., K.O.; Data Curation, C.B.M., M.C.C., L.J.H., K.O.; Writing—Original Draft Preparation, J.B.K..; Writing—Review & Editing, I.N., R.B., N.A.D., E.J.G., C.B.M.; Visualization, J.B.K., C.B.M., Supervision, C.B.M.; Project Administration, C.B.M.; Software, NA; Validation, NA; Formal analysis, NA; Investigation, NA; Resources, NA; Funding, NA. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
This report is a case study, therefore not meeting the Common Rule definition of research as it is not designed to develop generalizable knowledge and did not required ethical approval.
Informed Consent Statement
Given the retrospective nature of this report, the fatal outcome, and the lack of identifiable information, family was not contacted to obtain informed consent.
Conflicts of Interest
The authors declare no conflict of interest. Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
Appendix A
Briviact (brivaracetam injection) [package insert]. Smyrna, G. and I.R.M. UCB.
Cerebyx (fosphenytoin sodium injection) [package insert]. New York, N. and I.R.F. Pfizer.
Propofol injectable emulsion [package insert]. Lake Forest, I. and I.R.M. Hospira.
Ketalar (ketamine hydrochloride injection) [package Insert]. Chestnut Ridge, N., P. Pharmaceutical, and R.A. 2020.
Vimpat (lacosamide injection) [package insert]. Smyrna, G. and I.R.N. UCB.
Midazolam hydrochloride injection [package insert]. Lake Forest, I. and I.R. Hospira.
Thiopental sodium injection [package insert]. Galashiels, U. and L.R.O. Kyowa Kirin.
Valproate sodium injection [package insert]. Eatontown, N. and W.-W.P.C.R.M. 2019.
Sulfamethoxazole and trimethoprim injection [package insert]. Morgantown, W. and M.I.L.R.D. 2020.
Vancomycin hydrochloride for injection [package insert]. Rockford, I. and M.I.L.R.J. 2018.
Carbatrol (carbamazepine extended-release tablet) [package insert]. Lexington, M. and I.R.N. Takeda Pharmaceuticals America.
Levetiracetam immediate-release tablet [package insert]. Chestnut Ridge, N. and P.P.R.S. 2020.
Metamucil (psyllium husk powder) [product information]. Cincinnati, O. and P.G.R.D. 2019.
Divalproex sodium extended-release tablets [package insert]. Bridgewater, N. and A.P.L.R.A. 2020.
Peridex (chlorhexidine gluconate 0.12%) [package insert]. 3M Canada Company Dental Products. 2007.
Figure 1 Drug Interference with achievement of ketosis. Seizure Activity: On HD 14–16, seizure burden was 90% nonconvulsive status epilepticus (NCSE) and decreased to 10–15% by hospital day (HD) 23–24. From HD 30–39, % ictal ranged from 5–20% with HD 40 showing <1% ictal. % Ictal increased briefly during HD 41–47 with an average of 15% ictal but decreased to <1% by HD 48/49. % Ictal remained in the 10–20% range until HD 57 with % ictal < 1. From HD 58–72 % ictal ranged from 5–20% until % ictal <5 by HD 72.
jcm-10-00881-t001_Table 1Table 1 Summary work-up for New-Onset Refractory Status Epilepticus (NORSE) patient.
Categories Serum CSF Imaging Pathology
Infectious: Influenza A/B, H1N1, RPR, HIV, cat scratch panel, tick borne panel, Mycoplasma pneumonia, B Henselae, B quintana (all negative) West Nile Virus, Enterovirus, Bacterial culture, HSV, VZV, Lyme disease, fungal culture, HHV6, EBV, Mycoplasma pneumoniae (all negative)
Inflammatory: ANA, dsDNA, SSA, SSB, SCL 70, CRP, ESR, TPO antibody, thyroglobulin antibody, complements (C3, C4, CH50), ANCA, B2 glycoprotein, anticardiolipin, Antiribosomal P protein Ab, ACE, smooth muscle antibody, skeletal muscle antibody AMPA-R Ab, CASPR2 Ab, DPPX Ab, GABA-B-R Ab, GAD 65, GFAP, LGI1-IgG, mGluR1 Ab, NMDA R Ab
Paraneoplastic: GAD 65, NMDA, voltage gated potassium channel antibody, flow cytometry AChR ganglionic neuronal Ab, Amphiphysin Ab, Antiglial nuclear Ab, Antineuronal nuclear Ab, CRMP-5, Neuronal (V-G) K+ channel Ab, N-Type Calcium channel ab, P/Q type calcium channel Ab, Purkinje cell cytoplasmic Ab, Striational Ab (all negative)
Metabolic: TSH (0.22), Free T4 (1.7 ng/dL), Ammonia (47, 33, 37 µL/dL), serum and urine toxicology (negative)
MRI brain w/wo contrast: restricted diffusion and hyperintense FLAIR signal in the bilateral hippocampi Benign ovarian cyst
CT Chest/abdomen/pelvis: no evidence of ovarian teratoma or other malignancy No malignant cells in CSF
US pelvis: tiny 3–4 mm echogenic focus on the left ovary which may represent a small calcification, however, a tiny teratoma cannot be excluded
MRI pelvis: no evidence of ovarian teratoma
Work-up recommendations from Table 1 from Sculier C, Gaspard N. New onset refractory status epilepticus (NORSE). Seizure. 2019 May; 68:72–78. doi: 10.1016/j.seizure.2018.09.018. Epub 2018 Sep 29. PMID: 30482654. [18]. Influenza A/B: negative; H1N1: negative; Smooth and skeletal muscle antibody: negative; RPR: rapid plasma reagent—negative; ANA: antinuclear antibody—1:2560 titer; dsDNA: double-strand DNA—positive, 38.4 IU/mL; SSA: Sjögren’s Syndrome A—greater than 8; SSB: Sjögren’s Syndrome B—negative; SCL 70: Scleroderma (antitopoisomerase)—negative; Antiribosomal P protein—negative; CRP: C-reactive protein—54 mg/L; ESR: erythrocyte sedimentation rate—51 mm/h; C3/C4/CH50: within normal limits; B2 glycoprotein—negative; Anticardiolipin—negative; TPO: thyroperoxidase antibody—negative; thyroglobulin antibody—negative; ANCA: antineutrophil cytoplasmic antibody—negative; ACE: angiotensin converting enzyme—within normal limits; GAD 65: Glutamic acid decarboxylase—negative; NMDA: N-methyl-D-Aspartate receptor antibody—negative; AMPA: α-amino-3-hydroxy-5-methyl-4 -isoxazolepropionic acid receptor- antibody negative; TSH: thyroid stimulating hormone—within normal limits; HIV: Human immunodeficiency virus—negative; Lyme disease—negative; West Nile Virus—negative; Enterovirus- negative; Bacterial and fungal culture—negative; HSV: Herpes Simplex Virus—negative; VZV: Varicella Zoster Virus—negative; HHV6: Human Herpes Virus 6—negative; EBV: Epstein Barr Virus—negative; GFAP: Glial Fibrillary Acidic Protein—negative; LGI1: Leucine-rich glioma-inactivated—negative; CASPR2: Contactin-associated protein-like 2—negative; DPPX: dipeptidyl-peptidase-like protein 6—negative; GABA: gamma-aminobutyric acid—negative; mGlu1: metabotropic glutamate receptor 1—negative; CRMP-5: CV2/collapsin response mediator protein—negative; Voltage gated potassium channel—negative.
jcm-10-00881-t002_Table 2Table 2 Common antiseizure medications, medications utilized in hospitalized patients and associated carbohydrate, fat, and alcohol content.
Intravenous Product (General Product Concentration)
Carbohydrate Excipient and Amount Per Vial
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Brivaracetam (10 mg/mL) – – – –
Diazepam (5 mg/mL) [41] Propylene glycol: 414 mg 828 mg CHO/10 mg – 79 mg
Famotidine (10 mg/mL) [41] Mannitol: 20 mg 40 mg CHO/40 mg – –
Fosphenytoin [42] – – – –
Lorazepam (2 mg/mL) [42] Propylene glycol: 753 mg – – –
Pentobarbital (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Phenobarbital (130 mg/mL) [41] Propylene glycol: 702 mg – – 79 mg
Phenytoin (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Propofol (10 mg/mL) [41] Glycerol: 22.5 mg/mL 450 mg CHO/h
(20 mL/h) Soybean oil: 100 mg/mL Benzyl alcohol *
Egg Lecithin: 12 mg/mL
Lipid: 100 mg/mL
(1.1 kcal/mL)
Ketamine (multiple) – – – –
Lacosamide (multiple) – – – –
Midazolam (multiple) – – – Benzyl alcohol †
Thiopental (25 mg/mL) – – – –
Valproate (20 mg/mL) – – – –
Trimethoprim-sulfamethoxazole (Bactrim®) diluted in Dextrose 5% W 100 mL per 80–400 mg TMP-SMX Dextrose: 5 g/100 ml Up to 20 g CHO per dose – –
Vancomycin (Vancocin®) diluted in Dextrose 5% W per 1 g/250 mL solution Dextrose: 5 g/100 ml Up to 2 g CHO per dose – –
Enteral Product § (General Product Strength)
Carbohydrate Excipient and Amount Per Unit
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Carbamazepine (extended-release tablet) Lactose monohydrate ‡
Microcrystalline cellulose ‡ – – –
Clobazam (10 mg tablet) [43] 105.3 mg/tablet ≈100 mg/10 mg – –
Clonazepam (0.5 mg tablet) [43] 143.5 mg/tablet ≈2800 mg/10 mg – –
Levetiracetam (immediate release tablet) Croscarmellose sodium ‡
Polyethylene glycol 3350 ‡
Polyethylene glycol 6000 ‡ – – Polyvinyl alcohol
Psyllium (Metamucil) packet 9 g CHO/tablespoon 27 g CHO/day (TID) – –
Divalproex sodium (extended-release tablet) Hypromelloses ‡
Lactose monohydrate ‡
Polyethylene glycol ‡
Propylene glycol ‡
Macrogol ‡
Microcrystalline cellulose ‡ – – n-Butyl alcohol
Isopropyl alcohol
Polyvinyl alcohol
See Appendix A for package inserts. * Present at 1.5 mg/mL in all vial sizes (0.15% w/v). Avoid use in pediatric populations due to benzyl alcohol content. † Present at 10 mg/mL in all vial sizes (1% w/v), except preservative-free formulations. Avoid use in pediatric populations due to benzyl alcohol content. ‡ Unknown amount of relative excipient may affect ketosis but is likely clinically insignificant. § Solution and suspension formulations should be avoided if possible as they usually contain sugars that will affect ketosis.
jcm-10-00881-t003_Table 3Table 3 Ketogenic Diet checklist for Status Epilepticus.
Pearls to Consider for Starting and Maintaining a Ketogenic Diet (KD)
I. KD initiation
○ Check fasting lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D serum levels
○ Record baseline weight and height
○ Continuous video EEG
○ Dietitian/nutrition consult (consider pediatric nutritionist)
○ Stop current enteral formula
○ Reduce carbohydrate content in medications and parenteral fluids with pharmacy input
○ Active communication with nursing/pharmacy, EMR warnings, and signs in room are crucial to avoid medication/IV-containing carbohydrates
○ Begin KD (e.g., KetoCal/MCT oil)
○ Include multivitamin injection, Vit. D and calcium supplementation via nasogastric tube/gastric tube
○ Change any oral agents from liquid formulation to crushed tablet formulation
II. KD maintenance
○ Remove all common carbohydrate excipients in intravenous fluids, including:
○ Glycerin
○ Maltodextrin
○ Propylene glycol
○ Sugars (dextrose, fructose, glucose, lactose, sucrose, corn syrup)
○ Sugar alcohols (glycerol, mannitol, sorbitol)
○ Starches
○
KD can be challenged via coadministration of other meds & IVs!
III. Pitfalls to consider:
○ Contraindications: unstable metabolic derangements, hemodynamic instability, coagulopathy/bleeding diathesis, pancreatitis, liver failure, severe hyperlipidemia, ileus, pregnancy, known fatty acid oxidation disorder or pyruvate carboxylase deficiency
○
Propofol infusions cannot be given within 24 h before starting a KD!
Adapted & modified from Table 3 from Thakur KT, Probasco JC, Hocker SE, et al. Neurology. 2014 Feb 25; 82(8): 665–670. [4]. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33671485 | 19,466,490 | 2021-02-22 |
What was the dosage of drug 'ACYCLOVIR'? | Pearls and Pitfalls of Introducing Ketogenic Diet in Adult Status Epilepticus: A Practical Guide for the Intensivist.
Background: Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of a ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and effective. Methods: We describe our experience, including the challenges of achieving and maintaining ketosis, in an adult with new onset refractory status epilepticus (NORSE). Case Vignette: A previously healthy 29-year-old woman was admitted with cryptogenic NORSE following a febrile illness; course was complicated by prolonged super-refractory SE. A comprehensive work-up was notable only for mild cerebral spinal fluid (CSF) pleocytosis, elevated nonspecific serum inflammatory markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI). Repeat CSF testing was normal and serial MRIs demonstrated resolution of edema and diffusion restriction with progressive hippocampal and diffuse atrophy. She required prolonged therapeutic coma with high anesthetic infusion rates, 16 antiseizure drug (ASD) trials, empiric immunosuppression and partial bilateral oophorectomy. Enteral ketogenic formula was started on hospital day 28. However, sustained beta-hydroxybutyrate levels >2 mmol/L were only achieved 37 days later following a comprehensive adjustment of the care plan. KD was challenging to maintain in the intensive care unit (ICU) and was discontinued due to poor nutritional state and pressure ulcers. KD was restarted again in a non-ICU unit facilitating ASD tapering without re-emergence of SE. Discussion: There are inconspicuous carbohydrates in commonly administered medications for SE including antibiotics, electrolyte repletion formulations, different preparations of the same drug (i.e., parenteral, tablet, or suspension) and even solutions used for oral care-all challenging the use of KD in the hospitalized patient. Tailoring comprehensive care and awareness of possible complications of KD are important for the successful implementation and maintenance of ketosis.
1. Introduction
Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and potentially effective [1,2,3,4,5]. Most often used in childhood epilepsies, KD has emerged as a potential adjunctive treatment for pediatric SE [6,7]. We describe our experience with an adult with new onset refractory status epilepticus (NORSE) focusing on the unexpected challenge of achieving and maintaining ketosis. Practical advice, and a comprehensive review of factors potentially jeopardizing ketosis commonly encountered in the critical care setting and alternatives are provided.
2. Presentation
A previously healthy 29-year-old woman was admitted to another institution with new onset refractory status epilepticus (NORSE) following a febrile illness with a course complicated by prolonged super-refractory SE. Three days prior to presentation she developed fever, headache, emesis and fatigue in the setting of being in contact with her child with an upper respiratory tract infection. On the morning of admission, her friend attempted to awaken her for work and found her unresponsive and convulsing. In the emergency department, she was lethargic and mumbling incoherently. During her initial evaluation she had a witnessed 45-s bilateral tonic-clonic seizure that was aborted with 2 mg lorazepam intravenously. Head computed tomography was unremarkable and initial cerebrospinal fluid (CSF) analysis showed a mononuclear pleocytosis (2 RBC, 41 nucleated cells (57% mononuclear cells), glucose 93, protein 54)). A one-hour electroencephalogram (EEG) showed diffuse delta activity admixed with sleep spindles and K complexes without epileptiform discharges. She was monitored in the step-down unit and treated with levetiracetam and acyclovir. On hospital day two, she was somnolent but arousable to voice; she was able to follow simple midline commands, state her name and the current president, but was disoriented to time. She was noted to have twitching of her face, but no EEG was done at that time. By hospital day three, she began experiencing brief convulsive seizures which were aborted with intravenous lorazepam and always associated with recovery of consciousness. At that point, phenytoin (1 g loading dose, maintenance at 100 mg q8h) was added to her antiseizure drug (ASD) regimen. On hospital day four, she had multiple convulsive seizures without return to baseline, complicated by acute hypoxic respiratory failure requiring intubation. She was transferred to the intensive care unit (ICU) where she was started on propofol, and valproic acid (20 mg/kg loading dose, maintenance at 750 mg Q8H) was added. Routine EEG captured multiple discrete right frontal and centrotemporal onset seizures correlating with episodes of face twitching. She was started on pentobarbital infusion (5 mg/kg bolus, maintenance at 1 mg/kg per hour) and transferred to our center for continuous EEG monitoring.
3. Question: How Is Prolonged Seizure Activity Classified and What Are Potential Etiologies to Be Considered?
According to the most recent classification set by The International League Against Epilepsy, SE is a “condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures” [8]. While operational SE definitions based on time-domains vary according to seizure type, it is generally accepted that convulsive seizure activity lasting either greater than 5 min continuously, or two or more seizures during which the individual does not recover to baseline between seizures, represents SE [8]. Inhibitory gamma-aminobutyric acid (GABA) neurons located in the pars reticulata of the substantia nigra are key in seizure termination [9]. During status epilepticus, marked alteration of GABA metabolism occurs in this region and results in disinhibition of excitatory pathways: GABA synthesis slows down [10]. GABA turnover time increases up to three-fold, [10] and GABA receptors (originally located in the surface of the cell membrane) migrate to the intracellular space within minutes of ongoing seizure activity [11,12,13]. Prompt initiation of abortive therapies is key, as the internalization of GABA receptors contributes to refractoriness to treatment.
Emergent administration of parenteral benzodiazepine (e.g., up to 0.1 mg/kg of lorazepam) is considered the first-line therapy for SE [14]. If a patient fails to respond to a benzodiazepine and a second appropriately selected and dosed ASD at adequate doses, they are in refractory status epilepticus (RSE). It has been reported that one in five RSE patients go on to develop super-refractory status epilepticus (SRSE), defined as (1) ongoing seizures lasting 24 h or more after onset of anesthetic therapy (i.e., propofol) or (2) recurrence of SE upon reduction or withdrawal of therapeutic anesthetic coma [15]. The clinical presentation of RSE in patients without overt acute or remote brain injury, prior epilepsy, or acute toxic/metabolic explanation is consistent with New Onset Refractory Status Epilepticus—NORSE [16]. Febrile Infection-Related Epilepsy Syndrome (FIRES) is a subset of NORSE, in which a febrile infectious illness precedes SE onset by 1–14 days [14,15,16]. Thus, our patient qualified as having the syndrome of FIRES as well as NORSE. Further, clinical criteria for unequivocal electroencephalographic status epilepticus in patients without known epileptic encephalopathy has been established in the Salzburg consensus: (1) repeating epileptiform discharges occurring >2.5 Hz, or (2) repeating epileptiform discharges occurring ≤2.5 Hz or rhythmic delta/theta activity >0.5 Hz plus (a) electroclinical response (improvement) following intravenous ASD challenge, (b) subtle clinical correlate associated with pattern, or (c) typical temporal and spatial evolution of pattern [17].
Determining the underlying etiology of SE may seem a daunting task. However, its importance in achieving seizure cessation cannot be underestimated. Outcome following SE is dependent on the etiology of seizures. Further, appropriately recognizing the electroclinical classification of seizures (i.e., identifying the seizure semiology and its electrographic signature) may not only help selection of therapy but also identify potential etiologies [8]. Among NORSE patients, an etiology is found in up to 50% of cases [16]. Of those with an identifiable cause, the majority (37%) had an autoimmune cause (both nonparaneoplatic and paraneoplastic), while 8% had a probable infectious cause [16]. Thus, if an autoimmune etiology is diagnosed or clinically suspected, immune modulating therapies such as high-dose corticosteroids, intravenous immunoglobulin (IVIg) or plasma exchange therapy, followed by monoclonal antibodies and/or interleukin inhibitors, should be considered early in the course.
Our patient underwent a comprehensive work-up to determine the etiology of NORSE, as summarized on Table 1, which was notable only for mild CSF pleocytosis, elevated nonspecific inflammatory serum markers and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI).
4. Question: What Are the Initial Steps in the Therapeutic Algorithm for Status Epilepticus?
Benzodiazepines are the first-line treatment for SE [14,19] with slower-acting, less sedating parenteral ASDs being the second line (e.g., phenytoin, fosphenytoin, valproate and levetiracetam; and possibly lacosamide and phenobarbital). The Established Status Epilepticus Treatment Trial (ESETT) found no difference in efficacy between fosphenytoin (20 mgPE/kg), valproate (40 mg/kg) and levetiracetam (60 mg/kg) in children, adults and older adults; these ASDs were able to abort SE within an hour in nearly 50% of patients [20]. Once the second-line, or a combination of medications, fails to result in seizure cessation, continuous intravenous infusions of anesthetics (i.e., midazolam, pentobarbital, propofol, ketamine) are often recommended [14,19].
In patients with SE, anesthetic use is associated with longer hospital stay, but not in-hospital or 90-day mortality [21]. Amongst NORSE patients who receive anesthetics, the mortality is high. However, the use of anesthetics is not associated with poor outcome [16]. In 61 patients with RSE, those who underwent deep sedation (defined as either EEG showing burst suppression or isoelectric activity) had both poorer long-term prognosis and increased mortality [22]. Burst suppression on EEG is defined as intermittent alternating periods of low amplitudes (<10 uV for burst suppression; 10–20 uV for burst attenuation) interrupting a background, which may consist of waves of varying frequencies. Earlier attainment of burst suppression may allow for a more rapid anesthetic wean [23], and it is important to frequently monitor the EEG and titrate anesthetic dose as appropriate. The goal of anesthetic use in RSE is the resolution of epileptiform activity in order to avoid physiologic effects while the underlying cause is identified and treated [24,25].
In our case, 16 antiseizure drug trials in various combinations and high anesthetic infusion rates were attempted. RSE persisted despite 160 mg/h (2.5 mg/kg/h) of midazolam prompting the initiation of ketamine. Despite improved seizure burden following ketamine bolus (1.5 mg/kg), reemergence of SE occurred despite up-titration of ketamine to our maximum infusion rate (7.5 mg/kg/h). Her EEG responded to propofol and pentobarbital with long periods of suppression, although her background remained with abundant generalized periodic discharges (GPD) at 2.5–3 Hz, qualifying as ongoing electrographic SE. [17,26] Burst suppression was eventually achieved with pentobarbital at 3 mg/kg/h and propofol at 40 mcg/kg/min. However, due to re-emergence of 2 Hz GPDs along with breakthrough seizures on attempted wean, she remained in a medically induced coma for over three months.
5. Question: What Are Potential Rescue Therapeutic Approaches to the Management of Super-Refractory Status Epilepticus?
Refractory and super-refractory SE and their complications are associated with significant morbidity including death, neuronal damage and systemic complications like cardiomyopathy, ischemic bowel, pulmonary edema and renal failure [27]. This highlights the necessity for a prompt and aggressive treatment approach. In the setting of treatment failure, alternative treatment options include inhaled anesthetics, magnesium infusion, pyridoxine, hypothermia, electrical and magnetic stimulation, additional immunotherapy, enteral ASDs and the KD [28].
Given a high suspicion for an autoimmune process, our patient was treated with intravenous methylprednisolone (1 g daily for 5 days), IVIg, plasma exchange and cyclophosphamide. Serial MRIs demonstrated resolution of edema and diffusion restriction with gradually progressive atrophy, predominantly in the hippocampi, and repeat CSF analysis was normal. She underwent empiric bilateral partial oophorectomy for an echogenic focus in her left ovary and concern for possible occult microteratoma, possibly secondary to N-methyl-D-Aspartate (NMDA) encephalitis (NMDA CSF < 1:1 and serum < 1:10) [29].
6. Ketogenic Diet
Ketosis is commonly defined as sustained beta-hydroxybutyrate levels > 2 mmol/L [30] or a urinary acetoacetate level of >40 mg/dL [31]. There is evidence supporting the use of KD in children with autoimmune epilepsies, symptomatic epilepsy syndromes, pediatric refractory and super-refractory SE [6,32]. In a study of 10 children (age six months—16 years old) with refractory focal SE, initiation of a KD resulted in lower seizure burden (50% reduction in seizures for 70% of the cohort) and resolution of seizures in 20% [6]. In the minority of patients with less than 50% seizure reduction (n = 3), severe adverse events (pancreatitis or severe vomiting and hypoglycemia) prompted KD discontinuation. In another study of 12 children with fever induced refractory epileptic encephalopathy, KD was able to stop seizures within two days following ketonuria [32]. Nevertheless, the side effects of KD limit its widespread use, and successful ketosis must be attained for seizure control.
More recently, KD has been evaluated in adult patients; a systematic review of 38 adult patients with RSE or SRSE demonstrated that 82% were able to achieve SE cessation with KD [33]. There are several complex mechanisms for the efficacious effect of KD on reducing seizure activity, which result from reduction in glucose intake, ketone body production and alteration of the gut microbiome. The metabolic changes induced by KD alter the balance of excitatory and inhibitory neurotransmitters, lead to reductions in oxidative stress and systemic as well as neuroinflammation, and have further long-term effects on gene expression [3,34].
We sought KD as a rescue therapy after conventional treatments had failed.
7. Question: What Are Some Factors Should the Clinician Consider When Selecting and Initiating KD for Adults with SE?
Initiating KD Safely
Determining the optimal patient for whom to implement KD requires a comprehensive evaluation of the patient’s past medical history, comorbidities and current clinical status. As with all treatment strategies, particularly in the ICU setting, a thoughtful risk-benefit analysis is warranted. Inborn errors of metabolism are a contraindication to KD [35,36]. However, these conditions most often present in early childhood, and rarely in adults, so screening is not routinely obtained prior to KD initiation in adults [1,2]. Other contraindications of KD include unstable metabolic (mitochondrial enzyme deficiencies) conditions, liver failure, acute pancreatitis, pregnancy and an inability to tolerate enteral feeds [5]. Protocols typically avoid starting KD within 24 h of propofol infusions to avoid possibly fatal propofol infusion syndrome, characterized by metabolic acidosis, lipemia, rhabdomyolysis and myocardial failure [37].
8. Question: Should You Fast the Patient to Achieve Ketosis Quickly? If So, How Long and What Are Potential Consequences? If You Decide Not to Fast, Can Ketosis Still Be Achieved?
Variations in KD Protocols
Historically, KD implementation in the setting of childhood epilepsy included an initial fasting period ranging anywhere from 12 [7] to 48 [36,38] hours or more. Once satisfactory ketosis is achieved, ketogenic formulations or meals (typically 4:1 g of fat: carbohydrate + protein ratio) can then be titrated as tolerated until full caloric requirements are met. To avoid potential complications of a fasting period (e.g., dehydration, hypoglycemia), Kim et al. began KD without initial fasting and found equivalency in time to ketosis and seizure reduction in 41 children with intractable epilepsy compared to a retrospective control population of 83 children who fasted prior to KD initiation [39]. While rates of hypoglycemia were similar when compared to controls, there were reduced rates of dehydration and reduced length of hospital stay.
An alternative, yet equally efficacious approach for childhood epilepsy, does not involve initial fasting or limiting caloric intake. This protocol differs from others in the fact that there is a gradual increase from 1:1 to 2:1 until the goal 4:1 ratio is reached [38]. This gradual induction and establishment of ketosis in children diagnosed with intractable epilepsy showed an equal reduction in seizure activity yet decreased weight loss and episodes of hypoglycemia, acidosis and dehydration. Nevertheless, since time is a major factor in terms of avoiding neurologic and systemic consequences of SE, a more aggressive approach to KD initiation (i.e., fasting and/or more rapidly advancing to full calories as tolerated) may be warranted in this setting.
Individual patient characteristics including age, illness severity, duration of anesthetic use prior to diet initiation resulting in reduction in gastrointestinal motility, and diet complications, may not allow the luxury of initiating a preferred protocol with certain ketogenic ratio or at a faster rate. This was evident in Cobo’s pediatric SRSE study in which ratios were started as low as 0.75:1 in some instances, and ratios never exceeding 2:1 in some cases [7]. The need for higher protein intake (often in cases of poor wound healing, malnutrition and/or low basal resting energy expenditure) challenges the use of higher fat:protein + carbohydrate ratios, although this is more of a concern with chronic KD use rather than in the acute setting of RSE and SRSE. A possible way to maximize ketosis when using lower ratios (thus, higher protein intake) is the addition of medium-chain triglyceride oils as they yield greater amounts of ketones/kcal of energy than longer chain varieties [36].
We used these principles, most frequently used in the setting of childhood epilepsy, to initiate KD for our NORSE patient with the goal of achieving ketosis quickly. Our patient was initially started on KD on hospital day 28 (HD 28) with a goal of 5:1 ratio (KetoCal® 4:1 at 55 mL/h plus 33 mL medium-chain triglycerides (MCT) oil to balance carbohydrate intake from medications, documented as 51 g daily on HD 30). At this time, supplemental protein via PROsource® was discontinued to assist with achieving ketosis. On HD 35, beta-hydroxybutyrate (BHB) levels continued to show inadequate ketosis [Figure 1] prompting the increase to 6:1 with additional MCT Oil. Through HD 65, beta-hydroxybutyrate continued to fluctuate below the 2.0 goal. On HD 71, beta-hydroxybutyrate again dropped with the only documented potential carbohydrate source (at that time) being a milk and molasses enema administered by a care team to alleviate constipation. The decision was made to return to a higher carbohydrate-containing formula and refocus nutrition goals on wound healing. At this time, our patient was identified as meeting the criteria for severe malnutrition based on weight loss of >7.5% in three months and limited energy intake for greater than or equal to five days [40].
9. Question: What Factors Can Impede the Success of Achieving Ketosis, and thus Jeopardize the Utility of KD?
Despite initiating KD with complete enteral feeds on hospital day 28, our patient was only able to reach ketosis a significant 37 days later (Figure 1). After a comprehensive assessment of the care plan, the culprit was found: inconspicuous carbohydrate-containing medications, infusions and oral-care solutions routinely given in the setting of a neurological ICU (Table 2).
10. Hidden Carbohydrates Can Hinder Achievement of Ketosis
In our experience, the most likely medication-induced barriers to ketosis include sedatives, antiseizure drugs and antibiotics. Benzodiazepines are not created equally when it comes to hidden/nonobvious carbohydrate content. Diazepam (Valium® 5 mg/mL) and Lorazepam (Ativan® 2 mg/mL) have been shown to have 40% and 80% propylene glycol content, respectively, which equates to an overall carbohydrate content of 0.4 g/mL and 0.8 g/mL [42]. Intake of this carbohydrate content in patients with status epilepticus on KD may hinder achieving ketosis, but can also precipitate propylene glycol toxicity and associated anion-gap, metabolic acidosis [44].
While the carbohydrate load of each individual dose may be inconsequential, the cumulative dose given to patients in extended hospital stays may be significant. For example, initial administrations of injectable lorazepam, 2 mg every 6 h yields approximately 3 g of carbohydrate per day [44]. For context, this patient’s energy assessment used an ideal body weight of 64.5 kg, with daily caloric requirements calculated to total 2260 kcal/day (35 kcal/kg). Using KD at a 4:1 ratio (a common target for KD), the macronutrient breakdown is 226 g fat, 51.6 g protein, and 4.9 g carbohydrates. Thus, lorazepam would have contributed over half of the allotted daily carbohydrate load. Figure 1 shows several instances where lorazepam administration was associated with significant troughs in beta-hydroxybutyrate levels. When benzodiazepine infusions are warranted for refractory cases, our recommendation would be to consider midazolam as an alternative; midazolam does not have propylene glycol in its formulation, resulting in lower rates of anion-gap metabolic acidosis [45]. Regarding enteral administration of benzodiazepines, it is worth noting that clobazam (Onfi ®) and clonazepam (Klonopin®) contain 105 mg and 143.5 mg of carbohydrates (i.e., lactose, starch) per 10 mg/0.5 mg tablet, respectively [Table 2]. When selecting benzodiazepines for treatment of SE in patients treated with KD, it is important to evaluate the carbohydrate content for the selected benzodiazepine and the administration method. Generally, solutions and suspensions should be avoided due to high carbohydrate containing excipients.
Another class of widely used sedatives, often with the potential to inadvertently hinder beta-hydroxybutyrate levels, are the barbiturates, particularly pentobarbital (Nembutal® 50 mg/mL) and phenobarbital (Phenobarb® 130 mg/mL). Barbiturates are commonly used in RSE. However, they have a high propylene glycol content (pentobarbital 414 mg/50 mg vial, phenobarbital 702 mg/130 mg vial [42] amounting to an overall carbohydrate content of 2.9 g/h when pentobarbital is infused at a rate of 5 mg/kg/h for a 70 kg patient) [Table 2]. We suggest that ketamine (and midazolam, as discussed above) be considered as an alternative to pentobarbital in patients with status epilepticus on KD, given their lack of propylene glycol [46], This same concept can be applied for phenytoin (Dilantin® 50 mg/mL), which contains 40% propylene glycol [42] amounting to a carbohydrate content of 414 mg (plus an additional 79 mg of alcohol). These principles can be observed in Figure 1 where beta-hydroxybutyrate levels drop on HD 52, corresponding with a phenobarbital load (a disruption in feeds also occurred to administer phenytoin by mouth). We recommend that fosphenytoin be used instead to avoid propylene glycol excipients (Table 2). Similarly, on HD 56, beta-hydroxybutyrate dropped to 0.63 mmol/L with a medication review showing intravenous phenobarbital administered overnight. Lastly, another note of caution regarding anesthetic infusions: propofol contains 1.1 kcal/mL (mostly from fats), which provides approximately 528 kcal per day (presuming 20 mL/h). While this increased caloric load may aid in ketosis, its 450 mg of glycerol per 20 mL vial may hinder ketosis (Table 2).
11. Noncarbohydrate Related Hindrance of Ketosis
Among children with refractory epilepsy, concomitant lamotrigine use decreases KD’s efficacy in seizure reduction [47]. This may be explained by ketosis increasing the metabolism/inactivation of lamotrigine via glucosyltransferases, which ultimately results in increased glutamate release. Lastly, one must not forget that while medication use can influence KD, the inverse is also true. While most serum concentrations of ASD were not found to significantly change upon KD use, valproic acid levels have been shown to decrease [48]. Therefore, it is recommended to monitor valproic acid while using KD therapy.
12. Question: Aside from Sedative Agents, What Other Widely Used Agents in the Neurological ICU Can Hinder Ketosis?
12.1. Antimicrobials and Respective Diluents as Source of Carbohydrates
Various antibiotics that are used frequently in the neurological ICU [49,50] can hinder ketosis. Intravenous trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim®) requires reconstitution with dextrose 5% water and, similarly, vancomycin is often diluted in dextrose 5% water prior to intravenous administration (Table 2). Figure 1 (line graph) shows several instances in which administration of TMP-SMX and vancomycin were associated with troughs in beta-hydroxybutyrate levels.
12.2. Non “Medications” Contain Hidden Carbohydrates
Hidden carbohydrates are found in oral care solutions such as chlorhexidine, dietary supplements and fiber. Chlorhexidine 0.12% oral solution (PeridexTM), reported to be superior to toothbrushing at reducing early ventilator-associated pneumonia [51], contains glycerin and ethyl alcohol (see Appendix A), both carbohydrate-containing substances that can affect KD [52]. Oral fiber supplements, such as psyllium, have a significant carbohydrate load (e.g., 9 g/tablespoon) (Table 2). However, as fiber has a lower glycemic index compared to other carbohydrate-containing sources in the ICU setting, it may still be used in some instances to counteract constipation.
12.3. Comprehensive Approach to Implementing KD in Adult SE
Adopting a systematic approach is key for the successful implementation and maintenance of a ketotic state. A checklist is provided in Table 3 with a summary of the suggested steps for successful KD initiation [4].
13. Question: What Laboratory Values Should the Intensivist Pay Particular Attention to When Using KD?
Baseline assessment of certain serum (lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D, and free and total carnitine) [41] and anthropometric (weight, height) parameters [5,33,53] are imperative to effectively see how values trend overtime with KD. This objective data collected longitudinally allows monitoring of metabolic and systemic side effects of KD to allow for cessation if need-be.
After deciding that KD is appropriate, the next step is to carefully review all standing orders in the patient’s chart to identify potential sources of hidden carbohydrates and replace with alternatives. Guidance by the dietary/nutrition team as well as an ICU pharmacist are recommended to improve success with achieving and maintaining ketosis. If possible, a nutritionist with knowledge and experience with managing a KD is preferred, which may necessitate involving the pediatric nutrition team.
In the critical care setting, nutrition is often dictated by the critical care team via administration of formula tube feeding, and patient compliance is not a key factor for achieving ketosis. Route of administration does impact ketosis as suspension or elixir medications, [53] the preferred formulations via percutaneous gastrostomies (PEG) or other enteral routes, must be replaced by alternative formulations with lower carbohydrate content [7]. Additionally, dextrose-free diluents [52] must be used whenever able in intravenous drug formulations. Unavoidable carbohydrates can be balanced with a calculated dose of fat in the form of MCT oil or a commercially available emulsified oil (provided that this addition coincides with caloric and macronutrient percentages discussed later). Additionally, this puts the patient at an increased risk for gastrointestinal complications such as steatorrhea, emesis and reflux.
14. Ketosis Maintenance and Surveillance
Inducing ketosis is only the first step in tackling SE. While a ketotic state is commonly defined as beta-hydroxybutyrate >2 mmol/L [30], similarly to antiseizure drugs, some individuals require higher level of ketosis (or antiseizure drugs) to achieve optimal seizure control. Thus, individual thresholds for optimal ketotic state may vary. In the presented case, the best therapeutic effect was noted with beta-hydroxybutyrate >3.5. Maintaining ketosis above a certain therapeutic level proves to be difficult, particularly when higher targets are required such as >3 mmol/L beta-hydroxybutyrate [7]. For example, Cobo’s case series illustrated that children with SRSE can have sudden, unexplained drops in beta-hydroxybutyrate levels.
After KD was stopped on HD 73 due to poor nutritional status, KD was reinitiated on HD 106 as the patient was no longer on bolus medications with high carbohydrate content. Ketosis was achieved rapidly over two days, with a beta-hydroxybutyrate of 2.34 mmol/L target once the goal of 6:1 ratio 18 kcal/kg was reached. The rapid achievement of ketotic state likely resulted from several days of fasting prior to its initiation in the setting of percutaneous gastrostomy placement and enterocutaneous fistula repair. The patient remained in ketosis, with beta-hydroxybutyrate levels fluctuating between 1.93–5.32 mmol/L, during which time seizures were best controlled when beta-hydroxybutyrate levels were >3.5 mmol/L.
Constant evaluation and re-evaluation of patient intake, including intravenous fluids, must be conducted. It is imperative to remove all common exogenous carbohydrates including glycerin, maltodextrin, propylene glycol, dextrose, fructose, glucose, lactose, sucrose, corn syrup, sugar alcohols and starches [52]. Appropriate alternatives include normal saline, balanced crystalloid or lactated Ringer’s solution.
15. Question: What Natural Physiologic Mechanisms Must Be Accounted for When Attempting to Achieve/Maintain Ketosis?
In addition to exogenous carbohydrate management, the intensivist must not overlook endogenous perturbations of glucose homeostasis. Commonly measured anywhere from every four [54] to eight hours after initiation of KD [7], fluctuations are commonly seen in the pediatric population as the clinician attempts to titrate to a glucose target level of 60–79 mg/dL [7]. While the lower limit of 40 mg/dL is referenced in the Academy of Nutrition and Dietetics Practice Paper, the clinicians at Yale New Haven Hospital use a slightly higher limit of 50 mg/dL when evaluating for KD initiation. Ketosis can be threatened by endogenous gluconeogenesis occurring during infection or injury [55]. The topic of glucose perturbations brings up the discussion of whether the use of glucocorticoids concurrently with KD hinders the diet’s efficacy. Among children with epilepsy being treated with KD, there have been reports of glucocorticoid use (even inhaled) being associated with seizure return, elevated glucose and ketosis hindrance [56]. More studies are needed to examine the relationships of KD and glucocorticoid use in the setting of SE/RSE.
16. KD and Supplements
Question: What Supplements may Be Warranted when Starting a Ketogenic Diet?
The KD’s inherent shift into fatty acid beta-oxidation predisposes to metabolic acidosis, which can be further compounded if individuals are fasting to achieve ketosis [36]. For these reasons, adequate bicarbonate levels (commonly >17 mmol/L) [7] should be ensured with concomitant sodium bicarbonate [5] and/or potassium citrate supplementation [7].
Beta-oxidation in the mitochondria is reliant on the adequate transport of long-chain fatty acids across the mitochondrial membrane via carnitine [36,53]. Carnitine supplementation is recommended when levels are low (<30 μmol/L) or if the patient is symptomatic, defined by lethargy, weakness and GI symptoms, which are often difficult to assess in a comatose patient [7,36,53]. Carnitine supplementation remains controversial, as levels poorly correlate with tissue stores and symptoms of carnitine deficiency may be difficult to identify in comatose patients [53].
Lastly, it is recommended that a low carbohydrate multivitamin, calcium carbonate and Vitamin D be added [34,36] via nasogastric/gastric tube (NG/G-tube). Most commercially available ketogenic formulas have the recommended daily allowance of these substances. Children with epilepsy have hypovitaminosis D (50%) and are at risk for osteoporosis [36,53]. Phosphorous, [53] administered separately to avoid calcium chelation, is a recommended supplement for its role in bone homeostasis. Lastly, it is our recommendation to supplement either lite salt or table salt for patients that have hyponatremia despite administration of sodium containing intravenous fluids.
17. Termination of Ketotic Therapy
Question: Once Anesthetics Have Been Weaned and/or Seizure Activity Has Improved, How Should KD Be Weaned?
Reasons for diet discontinuation include lack of response, development of complications and need for optimization of nutritional status. There are no clear guidelines to define a clear response to KD, as diseases and patient populations are very heterogeneous, and a clear absolute seizure cessation effect may not be seen. In some cases, allowing for anesthetic wean or antiseizure regimen simplification may be considered successful results. It is our recommendation that before considering therapeutic failure, higher ketotic levels should be pursued if the patient is able to tolerate a more aggressive titration of the KD, as patients, such as our patient, may respond to higher beta-hydroxybutyrate levels.
Like any antiseizure therapy, it is generally recommended to wean the KD diet gradually due to the historical thought that abrupt withdrawal of ketosis can precipitate recurrence of seizures or SE. Abrupt withdrawal of KD is recommended for emergencies only. Thus, gradually reducing the ratio of grams of fats:protein + carbohydrates is recommended (i.e., 4:1 to 3:1 to 2:1) [36]. Despite there being a common notion that overzealous weaning of KD can precipitate previously suppressed seizure activity, a study of over 183 children showed no significant difference in the incidence of seizures worsening between discontinuation/weaning rates (i.e., <1 week vs. 1–6 weeks vs. >6 weeks) [57]. However, there was an increase in seizure activity with faster weaning schedules among a particular cohort: children who had higher percentage (55–90%) of seizure reduction while on the KD. Additionally, among children who successfully stopped KD after seizure cessation, 42% of them were unable to achieve symptom improvement with either ASD or reinitiating of KD upon seizure relapse [58].
We recommend that the clinician use the KD’s treatment success as well as clinical judgement in adopting an individualized weaning schedule. Beginning on HD 194, our patient was weaned from the KD over five days by decreasing the ketogenic formula by 20% every 24 h and replacing it with a traditional critical care formula. Supplemental MCT oil was decreased at the beginning of the weaning process. No complications arose during this transition. Once able to tolerate oral nutrition, the patient will have the autonomy to determine whether to continue KD and contingency plans, such as offering a less strict KD therapy (modified Atkins diet, modified KD), which may be a reasonable alternative.
18. Anticipating and Managing Complications
Question: What Are Some Potential Complications of KD?
Complications of KD are not uncommon and may result in discontinuation of the diet. In the pediatric literature, 30 [6] to 38% discontinuation rates [59] are described due to inability to tolerate the diet or due to complications. These complications include metabolic derangements like dyslipidemia and hyperuricemia, gastrointestinal symptoms, renal stones, osteopenia and cardiac problems like QT prolongation and cardiomyopathy [36,59]. An uncommon yet reported complication is protein-losing enteropathy [60], and while this can be corrected for by cessation of KD, the likely consequence is an increase in seizures. Like osteoporosis and Vitamin D alterations, which may not be relevant in the setting of acute KD administration for RSE, these complications are less relevant in the setting of short-term KD. Rather, more relevant complications to be aware of include dehydration, hyponatremia, metabolic acidosis, hypoglycemia, gastroparesis and nausea/vomiting [5,59].
Aside from poor wound healing and critical illness myopathy, our NORSE patient tolerated KD well and was discharged after 218 days in the hospital. Additional longitudinal studies are needed to examine long-term sequelae of a high fat diet in the context of adults with SE. Future research may focus on complication rates specifically associated with acute administration of KD for adult patients with RSE/SRSE in the neurological ICU setting, as well as cessation upon symptom improvement. Our patient’s neurological examination at discharge was significant for spontaneous eye opening, orientated x 2, minimally talkative with soft but clear speech. She was able to follow simple commands like closing her eyes and wiggle her toes. Strength was 3/5 proximal upper extremity with 2/5 in distal upper and proximal lower extremity. The patient was readmitted three weeks later for cardiac arrest, with subsequent reemergence of status epilepticus. Despite EEG improvement on restarting KD, the patient was eventually transitioned to comfort measures only.
19. Future of KD in Adult SE/RSE/SRSE/NORSE
While the utility of KD in adult populations is certainly promising for the management of RSE and SRSE, there remain several gaps, including a lack of standardized treatment approach, lack of randomized, double-blind controlled studies and hidden carbohydrate sources, which may impair production of ketone bodies. These inconspicuous carbohydrates are found in commonly administered medications for SE including benzodiazepines, antibiotics, electrolyte repletion formulations and even solutions used for oral care. This review offers a brief outline of treatment strategies for KD use in adults and a systematic approach for successfully achieving, maintaining and eliminating ketosis.
Acknowledgments
Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
Conceptualization, C.B.M., J.B.K., K.O.; Methodology, C.B.M., J.B.K., K.O.; Data Curation, C.B.M., M.C.C., L.J.H., K.O.; Writing—Original Draft Preparation, J.B.K..; Writing—Review & Editing, I.N., R.B., N.A.D., E.J.G., C.B.M.; Visualization, J.B.K., C.B.M., Supervision, C.B.M.; Project Administration, C.B.M.; Software, NA; Validation, NA; Formal analysis, NA; Investigation, NA; Resources, NA; Funding, NA. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
This report is a case study, therefore not meeting the Common Rule definition of research as it is not designed to develop generalizable knowledge and did not required ethical approval.
Informed Consent Statement
Given the retrospective nature of this report, the fatal outcome, and the lack of identifiable information, family was not contacted to obtain informed consent.
Conflicts of Interest
The authors declare no conflict of interest. Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
Appendix A
Briviact (brivaracetam injection) [package insert]. Smyrna, G. and I.R.M. UCB.
Cerebyx (fosphenytoin sodium injection) [package insert]. New York, N. and I.R.F. Pfizer.
Propofol injectable emulsion [package insert]. Lake Forest, I. and I.R.M. Hospira.
Ketalar (ketamine hydrochloride injection) [package Insert]. Chestnut Ridge, N., P. Pharmaceutical, and R.A. 2020.
Vimpat (lacosamide injection) [package insert]. Smyrna, G. and I.R.N. UCB.
Midazolam hydrochloride injection [package insert]. Lake Forest, I. and I.R. Hospira.
Thiopental sodium injection [package insert]. Galashiels, U. and L.R.O. Kyowa Kirin.
Valproate sodium injection [package insert]. Eatontown, N. and W.-W.P.C.R.M. 2019.
Sulfamethoxazole and trimethoprim injection [package insert]. Morgantown, W. and M.I.L.R.D. 2020.
Vancomycin hydrochloride for injection [package insert]. Rockford, I. and M.I.L.R.J. 2018.
Carbatrol (carbamazepine extended-release tablet) [package insert]. Lexington, M. and I.R.N. Takeda Pharmaceuticals America.
Levetiracetam immediate-release tablet [package insert]. Chestnut Ridge, N. and P.P.R.S. 2020.
Metamucil (psyllium husk powder) [product information]. Cincinnati, O. and P.G.R.D. 2019.
Divalproex sodium extended-release tablets [package insert]. Bridgewater, N. and A.P.L.R.A. 2020.
Peridex (chlorhexidine gluconate 0.12%) [package insert]. 3M Canada Company Dental Products. 2007.
Figure 1 Drug Interference with achievement of ketosis. Seizure Activity: On HD 14–16, seizure burden was 90% nonconvulsive status epilepticus (NCSE) and decreased to 10–15% by hospital day (HD) 23–24. From HD 30–39, % ictal ranged from 5–20% with HD 40 showing <1% ictal. % Ictal increased briefly during HD 41–47 with an average of 15% ictal but decreased to <1% by HD 48/49. % Ictal remained in the 10–20% range until HD 57 with % ictal < 1. From HD 58–72 % ictal ranged from 5–20% until % ictal <5 by HD 72.
jcm-10-00881-t001_Table 1Table 1 Summary work-up for New-Onset Refractory Status Epilepticus (NORSE) patient.
Categories Serum CSF Imaging Pathology
Infectious: Influenza A/B, H1N1, RPR, HIV, cat scratch panel, tick borne panel, Mycoplasma pneumonia, B Henselae, B quintana (all negative) West Nile Virus, Enterovirus, Bacterial culture, HSV, VZV, Lyme disease, fungal culture, HHV6, EBV, Mycoplasma pneumoniae (all negative)
Inflammatory: ANA, dsDNA, SSA, SSB, SCL 70, CRP, ESR, TPO antibody, thyroglobulin antibody, complements (C3, C4, CH50), ANCA, B2 glycoprotein, anticardiolipin, Antiribosomal P protein Ab, ACE, smooth muscle antibody, skeletal muscle antibody AMPA-R Ab, CASPR2 Ab, DPPX Ab, GABA-B-R Ab, GAD 65, GFAP, LGI1-IgG, mGluR1 Ab, NMDA R Ab
Paraneoplastic: GAD 65, NMDA, voltage gated potassium channel antibody, flow cytometry AChR ganglionic neuronal Ab, Amphiphysin Ab, Antiglial nuclear Ab, Antineuronal nuclear Ab, CRMP-5, Neuronal (V-G) K+ channel Ab, N-Type Calcium channel ab, P/Q type calcium channel Ab, Purkinje cell cytoplasmic Ab, Striational Ab (all negative)
Metabolic: TSH (0.22), Free T4 (1.7 ng/dL), Ammonia (47, 33, 37 µL/dL), serum and urine toxicology (negative)
MRI brain w/wo contrast: restricted diffusion and hyperintense FLAIR signal in the bilateral hippocampi Benign ovarian cyst
CT Chest/abdomen/pelvis: no evidence of ovarian teratoma or other malignancy No malignant cells in CSF
US pelvis: tiny 3–4 mm echogenic focus on the left ovary which may represent a small calcification, however, a tiny teratoma cannot be excluded
MRI pelvis: no evidence of ovarian teratoma
Work-up recommendations from Table 1 from Sculier C, Gaspard N. New onset refractory status epilepticus (NORSE). Seizure. 2019 May; 68:72–78. doi: 10.1016/j.seizure.2018.09.018. Epub 2018 Sep 29. PMID: 30482654. [18]. Influenza A/B: negative; H1N1: negative; Smooth and skeletal muscle antibody: negative; RPR: rapid plasma reagent—negative; ANA: antinuclear antibody—1:2560 titer; dsDNA: double-strand DNA—positive, 38.4 IU/mL; SSA: Sjögren’s Syndrome A—greater than 8; SSB: Sjögren’s Syndrome B—negative; SCL 70: Scleroderma (antitopoisomerase)—negative; Antiribosomal P protein—negative; CRP: C-reactive protein—54 mg/L; ESR: erythrocyte sedimentation rate—51 mm/h; C3/C4/CH50: within normal limits; B2 glycoprotein—negative; Anticardiolipin—negative; TPO: thyroperoxidase antibody—negative; thyroglobulin antibody—negative; ANCA: antineutrophil cytoplasmic antibody—negative; ACE: angiotensin converting enzyme—within normal limits; GAD 65: Glutamic acid decarboxylase—negative; NMDA: N-methyl-D-Aspartate receptor antibody—negative; AMPA: α-amino-3-hydroxy-5-methyl-4 -isoxazolepropionic acid receptor- antibody negative; TSH: thyroid stimulating hormone—within normal limits; HIV: Human immunodeficiency virus—negative; Lyme disease—negative; West Nile Virus—negative; Enterovirus- negative; Bacterial and fungal culture—negative; HSV: Herpes Simplex Virus—negative; VZV: Varicella Zoster Virus—negative; HHV6: Human Herpes Virus 6—negative; EBV: Epstein Barr Virus—negative; GFAP: Glial Fibrillary Acidic Protein—negative; LGI1: Leucine-rich glioma-inactivated—negative; CASPR2: Contactin-associated protein-like 2—negative; DPPX: dipeptidyl-peptidase-like protein 6—negative; GABA: gamma-aminobutyric acid—negative; mGlu1: metabotropic glutamate receptor 1—negative; CRMP-5: CV2/collapsin response mediator protein—negative; Voltage gated potassium channel—negative.
jcm-10-00881-t002_Table 2Table 2 Common antiseizure medications, medications utilized in hospitalized patients and associated carbohydrate, fat, and alcohol content.
Intravenous Product (General Product Concentration)
Carbohydrate Excipient and Amount Per Vial
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Brivaracetam (10 mg/mL) – – – –
Diazepam (5 mg/mL) [41] Propylene glycol: 414 mg 828 mg CHO/10 mg – 79 mg
Famotidine (10 mg/mL) [41] Mannitol: 20 mg 40 mg CHO/40 mg – –
Fosphenytoin [42] – – – –
Lorazepam (2 mg/mL) [42] Propylene glycol: 753 mg – – –
Pentobarbital (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Phenobarbital (130 mg/mL) [41] Propylene glycol: 702 mg – – 79 mg
Phenytoin (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Propofol (10 mg/mL) [41] Glycerol: 22.5 mg/mL 450 mg CHO/h
(20 mL/h) Soybean oil: 100 mg/mL Benzyl alcohol *
Egg Lecithin: 12 mg/mL
Lipid: 100 mg/mL
(1.1 kcal/mL)
Ketamine (multiple) – – – –
Lacosamide (multiple) – – – –
Midazolam (multiple) – – – Benzyl alcohol †
Thiopental (25 mg/mL) – – – –
Valproate (20 mg/mL) – – – –
Trimethoprim-sulfamethoxazole (Bactrim®) diluted in Dextrose 5% W 100 mL per 80–400 mg TMP-SMX Dextrose: 5 g/100 ml Up to 20 g CHO per dose – –
Vancomycin (Vancocin®) diluted in Dextrose 5% W per 1 g/250 mL solution Dextrose: 5 g/100 ml Up to 2 g CHO per dose – –
Enteral Product § (General Product Strength)
Carbohydrate Excipient and Amount Per Unit
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Carbamazepine (extended-release tablet) Lactose monohydrate ‡
Microcrystalline cellulose ‡ – – –
Clobazam (10 mg tablet) [43] 105.3 mg/tablet ≈100 mg/10 mg – –
Clonazepam (0.5 mg tablet) [43] 143.5 mg/tablet ≈2800 mg/10 mg – –
Levetiracetam (immediate release tablet) Croscarmellose sodium ‡
Polyethylene glycol 3350 ‡
Polyethylene glycol 6000 ‡ – – Polyvinyl alcohol
Psyllium (Metamucil) packet 9 g CHO/tablespoon 27 g CHO/day (TID) – –
Divalproex sodium (extended-release tablet) Hypromelloses ‡
Lactose monohydrate ‡
Polyethylene glycol ‡
Propylene glycol ‡
Macrogol ‡
Microcrystalline cellulose ‡ – – n-Butyl alcohol
Isopropyl alcohol
Polyvinyl alcohol
See Appendix A for package inserts. * Present at 1.5 mg/mL in all vial sizes (0.15% w/v). Avoid use in pediatric populations due to benzyl alcohol content. † Present at 10 mg/mL in all vial sizes (1% w/v), except preservative-free formulations. Avoid use in pediatric populations due to benzyl alcohol content. ‡ Unknown amount of relative excipient may affect ketosis but is likely clinically insignificant. § Solution and suspension formulations should be avoided if possible as they usually contain sugars that will affect ketosis.
jcm-10-00881-t003_Table 3Table 3 Ketogenic Diet checklist for Status Epilepticus.
Pearls to Consider for Starting and Maintaining a Ketogenic Diet (KD)
I. KD initiation
○ Check fasting lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D serum levels
○ Record baseline weight and height
○ Continuous video EEG
○ Dietitian/nutrition consult (consider pediatric nutritionist)
○ Stop current enteral formula
○ Reduce carbohydrate content in medications and parenteral fluids with pharmacy input
○ Active communication with nursing/pharmacy, EMR warnings, and signs in room are crucial to avoid medication/IV-containing carbohydrates
○ Begin KD (e.g., KetoCal/MCT oil)
○ Include multivitamin injection, Vit. D and calcium supplementation via nasogastric tube/gastric tube
○ Change any oral agents from liquid formulation to crushed tablet formulation
II. KD maintenance
○ Remove all common carbohydrate excipients in intravenous fluids, including:
○ Glycerin
○ Maltodextrin
○ Propylene glycol
○ Sugars (dextrose, fructose, glucose, lactose, sucrose, corn syrup)
○ Sugar alcohols (glycerol, mannitol, sorbitol)
○ Starches
○
KD can be challenged via coadministration of other meds & IVs!
III. Pitfalls to consider:
○ Contraindications: unstable metabolic derangements, hemodynamic instability, coagulopathy/bleeding diathesis, pancreatitis, liver failure, severe hyperlipidemia, ileus, pregnancy, known fatty acid oxidation disorder or pyruvate carboxylase deficiency
○
Propofol infusions cannot be given within 24 h before starting a KD!
Adapted & modified from Table 3 from Thakur KT, Probasco JC, Hocker SE, et al. Neurology. 2014 Feb 25; 82(8): 665–670. [4]. | UNKNOWN DOSE | DrugDosageText | CC BY | 33671485 | 19,466,490 | 2021-02-22 |
What was the dosage of drug 'LEVETIRACETAM'? | Pearls and Pitfalls of Introducing Ketogenic Diet in Adult Status Epilepticus: A Practical Guide for the Intensivist.
Background: Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of a ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and effective. Methods: We describe our experience, including the challenges of achieving and maintaining ketosis, in an adult with new onset refractory status epilepticus (NORSE). Case Vignette: A previously healthy 29-year-old woman was admitted with cryptogenic NORSE following a febrile illness; course was complicated by prolonged super-refractory SE. A comprehensive work-up was notable only for mild cerebral spinal fluid (CSF) pleocytosis, elevated nonspecific serum inflammatory markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI). Repeat CSF testing was normal and serial MRIs demonstrated resolution of edema and diffusion restriction with progressive hippocampal and diffuse atrophy. She required prolonged therapeutic coma with high anesthetic infusion rates, 16 antiseizure drug (ASD) trials, empiric immunosuppression and partial bilateral oophorectomy. Enteral ketogenic formula was started on hospital day 28. However, sustained beta-hydroxybutyrate levels >2 mmol/L were only achieved 37 days later following a comprehensive adjustment of the care plan. KD was challenging to maintain in the intensive care unit (ICU) and was discontinued due to poor nutritional state and pressure ulcers. KD was restarted again in a non-ICU unit facilitating ASD tapering without re-emergence of SE. Discussion: There are inconspicuous carbohydrates in commonly administered medications for SE including antibiotics, electrolyte repletion formulations, different preparations of the same drug (i.e., parenteral, tablet, or suspension) and even solutions used for oral care-all challenging the use of KD in the hospitalized patient. Tailoring comprehensive care and awareness of possible complications of KD are important for the successful implementation and maintenance of ketosis.
1. Introduction
Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and potentially effective [1,2,3,4,5]. Most often used in childhood epilepsies, KD has emerged as a potential adjunctive treatment for pediatric SE [6,7]. We describe our experience with an adult with new onset refractory status epilepticus (NORSE) focusing on the unexpected challenge of achieving and maintaining ketosis. Practical advice, and a comprehensive review of factors potentially jeopardizing ketosis commonly encountered in the critical care setting and alternatives are provided.
2. Presentation
A previously healthy 29-year-old woman was admitted to another institution with new onset refractory status epilepticus (NORSE) following a febrile illness with a course complicated by prolonged super-refractory SE. Three days prior to presentation she developed fever, headache, emesis and fatigue in the setting of being in contact with her child with an upper respiratory tract infection. On the morning of admission, her friend attempted to awaken her for work and found her unresponsive and convulsing. In the emergency department, she was lethargic and mumbling incoherently. During her initial evaluation she had a witnessed 45-s bilateral tonic-clonic seizure that was aborted with 2 mg lorazepam intravenously. Head computed tomography was unremarkable and initial cerebrospinal fluid (CSF) analysis showed a mononuclear pleocytosis (2 RBC, 41 nucleated cells (57% mononuclear cells), glucose 93, protein 54)). A one-hour electroencephalogram (EEG) showed diffuse delta activity admixed with sleep spindles and K complexes without epileptiform discharges. She was monitored in the step-down unit and treated with levetiracetam and acyclovir. On hospital day two, she was somnolent but arousable to voice; she was able to follow simple midline commands, state her name and the current president, but was disoriented to time. She was noted to have twitching of her face, but no EEG was done at that time. By hospital day three, she began experiencing brief convulsive seizures which were aborted with intravenous lorazepam and always associated with recovery of consciousness. At that point, phenytoin (1 g loading dose, maintenance at 100 mg q8h) was added to her antiseizure drug (ASD) regimen. On hospital day four, she had multiple convulsive seizures without return to baseline, complicated by acute hypoxic respiratory failure requiring intubation. She was transferred to the intensive care unit (ICU) where she was started on propofol, and valproic acid (20 mg/kg loading dose, maintenance at 750 mg Q8H) was added. Routine EEG captured multiple discrete right frontal and centrotemporal onset seizures correlating with episodes of face twitching. She was started on pentobarbital infusion (5 mg/kg bolus, maintenance at 1 mg/kg per hour) and transferred to our center for continuous EEG monitoring.
3. Question: How Is Prolonged Seizure Activity Classified and What Are Potential Etiologies to Be Considered?
According to the most recent classification set by The International League Against Epilepsy, SE is a “condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures” [8]. While operational SE definitions based on time-domains vary according to seizure type, it is generally accepted that convulsive seizure activity lasting either greater than 5 min continuously, or two or more seizures during which the individual does not recover to baseline between seizures, represents SE [8]. Inhibitory gamma-aminobutyric acid (GABA) neurons located in the pars reticulata of the substantia nigra are key in seizure termination [9]. During status epilepticus, marked alteration of GABA metabolism occurs in this region and results in disinhibition of excitatory pathways: GABA synthesis slows down [10]. GABA turnover time increases up to three-fold, [10] and GABA receptors (originally located in the surface of the cell membrane) migrate to the intracellular space within minutes of ongoing seizure activity [11,12,13]. Prompt initiation of abortive therapies is key, as the internalization of GABA receptors contributes to refractoriness to treatment.
Emergent administration of parenteral benzodiazepine (e.g., up to 0.1 mg/kg of lorazepam) is considered the first-line therapy for SE [14]. If a patient fails to respond to a benzodiazepine and a second appropriately selected and dosed ASD at adequate doses, they are in refractory status epilepticus (RSE). It has been reported that one in five RSE patients go on to develop super-refractory status epilepticus (SRSE), defined as (1) ongoing seizures lasting 24 h or more after onset of anesthetic therapy (i.e., propofol) or (2) recurrence of SE upon reduction or withdrawal of therapeutic anesthetic coma [15]. The clinical presentation of RSE in patients without overt acute or remote brain injury, prior epilepsy, or acute toxic/metabolic explanation is consistent with New Onset Refractory Status Epilepticus—NORSE [16]. Febrile Infection-Related Epilepsy Syndrome (FIRES) is a subset of NORSE, in which a febrile infectious illness precedes SE onset by 1–14 days [14,15,16]. Thus, our patient qualified as having the syndrome of FIRES as well as NORSE. Further, clinical criteria for unequivocal electroencephalographic status epilepticus in patients without known epileptic encephalopathy has been established in the Salzburg consensus: (1) repeating epileptiform discharges occurring >2.5 Hz, or (2) repeating epileptiform discharges occurring ≤2.5 Hz or rhythmic delta/theta activity >0.5 Hz plus (a) electroclinical response (improvement) following intravenous ASD challenge, (b) subtle clinical correlate associated with pattern, or (c) typical temporal and spatial evolution of pattern [17].
Determining the underlying etiology of SE may seem a daunting task. However, its importance in achieving seizure cessation cannot be underestimated. Outcome following SE is dependent on the etiology of seizures. Further, appropriately recognizing the electroclinical classification of seizures (i.e., identifying the seizure semiology and its electrographic signature) may not only help selection of therapy but also identify potential etiologies [8]. Among NORSE patients, an etiology is found in up to 50% of cases [16]. Of those with an identifiable cause, the majority (37%) had an autoimmune cause (both nonparaneoplatic and paraneoplastic), while 8% had a probable infectious cause [16]. Thus, if an autoimmune etiology is diagnosed or clinically suspected, immune modulating therapies such as high-dose corticosteroids, intravenous immunoglobulin (IVIg) or plasma exchange therapy, followed by monoclonal antibodies and/or interleukin inhibitors, should be considered early in the course.
Our patient underwent a comprehensive work-up to determine the etiology of NORSE, as summarized on Table 1, which was notable only for mild CSF pleocytosis, elevated nonspecific inflammatory serum markers and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI).
4. Question: What Are the Initial Steps in the Therapeutic Algorithm for Status Epilepticus?
Benzodiazepines are the first-line treatment for SE [14,19] with slower-acting, less sedating parenteral ASDs being the second line (e.g., phenytoin, fosphenytoin, valproate and levetiracetam; and possibly lacosamide and phenobarbital). The Established Status Epilepticus Treatment Trial (ESETT) found no difference in efficacy between fosphenytoin (20 mgPE/kg), valproate (40 mg/kg) and levetiracetam (60 mg/kg) in children, adults and older adults; these ASDs were able to abort SE within an hour in nearly 50% of patients [20]. Once the second-line, or a combination of medications, fails to result in seizure cessation, continuous intravenous infusions of anesthetics (i.e., midazolam, pentobarbital, propofol, ketamine) are often recommended [14,19].
In patients with SE, anesthetic use is associated with longer hospital stay, but not in-hospital or 90-day mortality [21]. Amongst NORSE patients who receive anesthetics, the mortality is high. However, the use of anesthetics is not associated with poor outcome [16]. In 61 patients with RSE, those who underwent deep sedation (defined as either EEG showing burst suppression or isoelectric activity) had both poorer long-term prognosis and increased mortality [22]. Burst suppression on EEG is defined as intermittent alternating periods of low amplitudes (<10 uV for burst suppression; 10–20 uV for burst attenuation) interrupting a background, which may consist of waves of varying frequencies. Earlier attainment of burst suppression may allow for a more rapid anesthetic wean [23], and it is important to frequently monitor the EEG and titrate anesthetic dose as appropriate. The goal of anesthetic use in RSE is the resolution of epileptiform activity in order to avoid physiologic effects while the underlying cause is identified and treated [24,25].
In our case, 16 antiseizure drug trials in various combinations and high anesthetic infusion rates were attempted. RSE persisted despite 160 mg/h (2.5 mg/kg/h) of midazolam prompting the initiation of ketamine. Despite improved seizure burden following ketamine bolus (1.5 mg/kg), reemergence of SE occurred despite up-titration of ketamine to our maximum infusion rate (7.5 mg/kg/h). Her EEG responded to propofol and pentobarbital with long periods of suppression, although her background remained with abundant generalized periodic discharges (GPD) at 2.5–3 Hz, qualifying as ongoing electrographic SE. [17,26] Burst suppression was eventually achieved with pentobarbital at 3 mg/kg/h and propofol at 40 mcg/kg/min. However, due to re-emergence of 2 Hz GPDs along with breakthrough seizures on attempted wean, she remained in a medically induced coma for over three months.
5. Question: What Are Potential Rescue Therapeutic Approaches to the Management of Super-Refractory Status Epilepticus?
Refractory and super-refractory SE and their complications are associated with significant morbidity including death, neuronal damage and systemic complications like cardiomyopathy, ischemic bowel, pulmonary edema and renal failure [27]. This highlights the necessity for a prompt and aggressive treatment approach. In the setting of treatment failure, alternative treatment options include inhaled anesthetics, magnesium infusion, pyridoxine, hypothermia, electrical and magnetic stimulation, additional immunotherapy, enteral ASDs and the KD [28].
Given a high suspicion for an autoimmune process, our patient was treated with intravenous methylprednisolone (1 g daily for 5 days), IVIg, plasma exchange and cyclophosphamide. Serial MRIs demonstrated resolution of edema and diffusion restriction with gradually progressive atrophy, predominantly in the hippocampi, and repeat CSF analysis was normal. She underwent empiric bilateral partial oophorectomy for an echogenic focus in her left ovary and concern for possible occult microteratoma, possibly secondary to N-methyl-D-Aspartate (NMDA) encephalitis (NMDA CSF < 1:1 and serum < 1:10) [29].
6. Ketogenic Diet
Ketosis is commonly defined as sustained beta-hydroxybutyrate levels > 2 mmol/L [30] or a urinary acetoacetate level of >40 mg/dL [31]. There is evidence supporting the use of KD in children with autoimmune epilepsies, symptomatic epilepsy syndromes, pediatric refractory and super-refractory SE [6,32]. In a study of 10 children (age six months—16 years old) with refractory focal SE, initiation of a KD resulted in lower seizure burden (50% reduction in seizures for 70% of the cohort) and resolution of seizures in 20% [6]. In the minority of patients with less than 50% seizure reduction (n = 3), severe adverse events (pancreatitis or severe vomiting and hypoglycemia) prompted KD discontinuation. In another study of 12 children with fever induced refractory epileptic encephalopathy, KD was able to stop seizures within two days following ketonuria [32]. Nevertheless, the side effects of KD limit its widespread use, and successful ketosis must be attained for seizure control.
More recently, KD has been evaluated in adult patients; a systematic review of 38 adult patients with RSE or SRSE demonstrated that 82% were able to achieve SE cessation with KD [33]. There are several complex mechanisms for the efficacious effect of KD on reducing seizure activity, which result from reduction in glucose intake, ketone body production and alteration of the gut microbiome. The metabolic changes induced by KD alter the balance of excitatory and inhibitory neurotransmitters, lead to reductions in oxidative stress and systemic as well as neuroinflammation, and have further long-term effects on gene expression [3,34].
We sought KD as a rescue therapy after conventional treatments had failed.
7. Question: What Are Some Factors Should the Clinician Consider When Selecting and Initiating KD for Adults with SE?
Initiating KD Safely
Determining the optimal patient for whom to implement KD requires a comprehensive evaluation of the patient’s past medical history, comorbidities and current clinical status. As with all treatment strategies, particularly in the ICU setting, a thoughtful risk-benefit analysis is warranted. Inborn errors of metabolism are a contraindication to KD [35,36]. However, these conditions most often present in early childhood, and rarely in adults, so screening is not routinely obtained prior to KD initiation in adults [1,2]. Other contraindications of KD include unstable metabolic (mitochondrial enzyme deficiencies) conditions, liver failure, acute pancreatitis, pregnancy and an inability to tolerate enteral feeds [5]. Protocols typically avoid starting KD within 24 h of propofol infusions to avoid possibly fatal propofol infusion syndrome, characterized by metabolic acidosis, lipemia, rhabdomyolysis and myocardial failure [37].
8. Question: Should You Fast the Patient to Achieve Ketosis Quickly? If So, How Long and What Are Potential Consequences? If You Decide Not to Fast, Can Ketosis Still Be Achieved?
Variations in KD Protocols
Historically, KD implementation in the setting of childhood epilepsy included an initial fasting period ranging anywhere from 12 [7] to 48 [36,38] hours or more. Once satisfactory ketosis is achieved, ketogenic formulations or meals (typically 4:1 g of fat: carbohydrate + protein ratio) can then be titrated as tolerated until full caloric requirements are met. To avoid potential complications of a fasting period (e.g., dehydration, hypoglycemia), Kim et al. began KD without initial fasting and found equivalency in time to ketosis and seizure reduction in 41 children with intractable epilepsy compared to a retrospective control population of 83 children who fasted prior to KD initiation [39]. While rates of hypoglycemia were similar when compared to controls, there were reduced rates of dehydration and reduced length of hospital stay.
An alternative, yet equally efficacious approach for childhood epilepsy, does not involve initial fasting or limiting caloric intake. This protocol differs from others in the fact that there is a gradual increase from 1:1 to 2:1 until the goal 4:1 ratio is reached [38]. This gradual induction and establishment of ketosis in children diagnosed with intractable epilepsy showed an equal reduction in seizure activity yet decreased weight loss and episodes of hypoglycemia, acidosis and dehydration. Nevertheless, since time is a major factor in terms of avoiding neurologic and systemic consequences of SE, a more aggressive approach to KD initiation (i.e., fasting and/or more rapidly advancing to full calories as tolerated) may be warranted in this setting.
Individual patient characteristics including age, illness severity, duration of anesthetic use prior to diet initiation resulting in reduction in gastrointestinal motility, and diet complications, may not allow the luxury of initiating a preferred protocol with certain ketogenic ratio or at a faster rate. This was evident in Cobo’s pediatric SRSE study in which ratios were started as low as 0.75:1 in some instances, and ratios never exceeding 2:1 in some cases [7]. The need for higher protein intake (often in cases of poor wound healing, malnutrition and/or low basal resting energy expenditure) challenges the use of higher fat:protein + carbohydrate ratios, although this is more of a concern with chronic KD use rather than in the acute setting of RSE and SRSE. A possible way to maximize ketosis when using lower ratios (thus, higher protein intake) is the addition of medium-chain triglyceride oils as they yield greater amounts of ketones/kcal of energy than longer chain varieties [36].
We used these principles, most frequently used in the setting of childhood epilepsy, to initiate KD for our NORSE patient with the goal of achieving ketosis quickly. Our patient was initially started on KD on hospital day 28 (HD 28) with a goal of 5:1 ratio (KetoCal® 4:1 at 55 mL/h plus 33 mL medium-chain triglycerides (MCT) oil to balance carbohydrate intake from medications, documented as 51 g daily on HD 30). At this time, supplemental protein via PROsource® was discontinued to assist with achieving ketosis. On HD 35, beta-hydroxybutyrate (BHB) levels continued to show inadequate ketosis [Figure 1] prompting the increase to 6:1 with additional MCT Oil. Through HD 65, beta-hydroxybutyrate continued to fluctuate below the 2.0 goal. On HD 71, beta-hydroxybutyrate again dropped with the only documented potential carbohydrate source (at that time) being a milk and molasses enema administered by a care team to alleviate constipation. The decision was made to return to a higher carbohydrate-containing formula and refocus nutrition goals on wound healing. At this time, our patient was identified as meeting the criteria for severe malnutrition based on weight loss of >7.5% in three months and limited energy intake for greater than or equal to five days [40].
9. Question: What Factors Can Impede the Success of Achieving Ketosis, and thus Jeopardize the Utility of KD?
Despite initiating KD with complete enteral feeds on hospital day 28, our patient was only able to reach ketosis a significant 37 days later (Figure 1). After a comprehensive assessment of the care plan, the culprit was found: inconspicuous carbohydrate-containing medications, infusions and oral-care solutions routinely given in the setting of a neurological ICU (Table 2).
10. Hidden Carbohydrates Can Hinder Achievement of Ketosis
In our experience, the most likely medication-induced barriers to ketosis include sedatives, antiseizure drugs and antibiotics. Benzodiazepines are not created equally when it comes to hidden/nonobvious carbohydrate content. Diazepam (Valium® 5 mg/mL) and Lorazepam (Ativan® 2 mg/mL) have been shown to have 40% and 80% propylene glycol content, respectively, which equates to an overall carbohydrate content of 0.4 g/mL and 0.8 g/mL [42]. Intake of this carbohydrate content in patients with status epilepticus on KD may hinder achieving ketosis, but can also precipitate propylene glycol toxicity and associated anion-gap, metabolic acidosis [44].
While the carbohydrate load of each individual dose may be inconsequential, the cumulative dose given to patients in extended hospital stays may be significant. For example, initial administrations of injectable lorazepam, 2 mg every 6 h yields approximately 3 g of carbohydrate per day [44]. For context, this patient’s energy assessment used an ideal body weight of 64.5 kg, with daily caloric requirements calculated to total 2260 kcal/day (35 kcal/kg). Using KD at a 4:1 ratio (a common target for KD), the macronutrient breakdown is 226 g fat, 51.6 g protein, and 4.9 g carbohydrates. Thus, lorazepam would have contributed over half of the allotted daily carbohydrate load. Figure 1 shows several instances where lorazepam administration was associated with significant troughs in beta-hydroxybutyrate levels. When benzodiazepine infusions are warranted for refractory cases, our recommendation would be to consider midazolam as an alternative; midazolam does not have propylene glycol in its formulation, resulting in lower rates of anion-gap metabolic acidosis [45]. Regarding enteral administration of benzodiazepines, it is worth noting that clobazam (Onfi ®) and clonazepam (Klonopin®) contain 105 mg and 143.5 mg of carbohydrates (i.e., lactose, starch) per 10 mg/0.5 mg tablet, respectively [Table 2]. When selecting benzodiazepines for treatment of SE in patients treated with KD, it is important to evaluate the carbohydrate content for the selected benzodiazepine and the administration method. Generally, solutions and suspensions should be avoided due to high carbohydrate containing excipients.
Another class of widely used sedatives, often with the potential to inadvertently hinder beta-hydroxybutyrate levels, are the barbiturates, particularly pentobarbital (Nembutal® 50 mg/mL) and phenobarbital (Phenobarb® 130 mg/mL). Barbiturates are commonly used in RSE. However, they have a high propylene glycol content (pentobarbital 414 mg/50 mg vial, phenobarbital 702 mg/130 mg vial [42] amounting to an overall carbohydrate content of 2.9 g/h when pentobarbital is infused at a rate of 5 mg/kg/h for a 70 kg patient) [Table 2]. We suggest that ketamine (and midazolam, as discussed above) be considered as an alternative to pentobarbital in patients with status epilepticus on KD, given their lack of propylene glycol [46], This same concept can be applied for phenytoin (Dilantin® 50 mg/mL), which contains 40% propylene glycol [42] amounting to a carbohydrate content of 414 mg (plus an additional 79 mg of alcohol). These principles can be observed in Figure 1 where beta-hydroxybutyrate levels drop on HD 52, corresponding with a phenobarbital load (a disruption in feeds also occurred to administer phenytoin by mouth). We recommend that fosphenytoin be used instead to avoid propylene glycol excipients (Table 2). Similarly, on HD 56, beta-hydroxybutyrate dropped to 0.63 mmol/L with a medication review showing intravenous phenobarbital administered overnight. Lastly, another note of caution regarding anesthetic infusions: propofol contains 1.1 kcal/mL (mostly from fats), which provides approximately 528 kcal per day (presuming 20 mL/h). While this increased caloric load may aid in ketosis, its 450 mg of glycerol per 20 mL vial may hinder ketosis (Table 2).
11. Noncarbohydrate Related Hindrance of Ketosis
Among children with refractory epilepsy, concomitant lamotrigine use decreases KD’s efficacy in seizure reduction [47]. This may be explained by ketosis increasing the metabolism/inactivation of lamotrigine via glucosyltransferases, which ultimately results in increased glutamate release. Lastly, one must not forget that while medication use can influence KD, the inverse is also true. While most serum concentrations of ASD were not found to significantly change upon KD use, valproic acid levels have been shown to decrease [48]. Therefore, it is recommended to monitor valproic acid while using KD therapy.
12. Question: Aside from Sedative Agents, What Other Widely Used Agents in the Neurological ICU Can Hinder Ketosis?
12.1. Antimicrobials and Respective Diluents as Source of Carbohydrates
Various antibiotics that are used frequently in the neurological ICU [49,50] can hinder ketosis. Intravenous trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim®) requires reconstitution with dextrose 5% water and, similarly, vancomycin is often diluted in dextrose 5% water prior to intravenous administration (Table 2). Figure 1 (line graph) shows several instances in which administration of TMP-SMX and vancomycin were associated with troughs in beta-hydroxybutyrate levels.
12.2. Non “Medications” Contain Hidden Carbohydrates
Hidden carbohydrates are found in oral care solutions such as chlorhexidine, dietary supplements and fiber. Chlorhexidine 0.12% oral solution (PeridexTM), reported to be superior to toothbrushing at reducing early ventilator-associated pneumonia [51], contains glycerin and ethyl alcohol (see Appendix A), both carbohydrate-containing substances that can affect KD [52]. Oral fiber supplements, such as psyllium, have a significant carbohydrate load (e.g., 9 g/tablespoon) (Table 2). However, as fiber has a lower glycemic index compared to other carbohydrate-containing sources in the ICU setting, it may still be used in some instances to counteract constipation.
12.3. Comprehensive Approach to Implementing KD in Adult SE
Adopting a systematic approach is key for the successful implementation and maintenance of a ketotic state. A checklist is provided in Table 3 with a summary of the suggested steps for successful KD initiation [4].
13. Question: What Laboratory Values Should the Intensivist Pay Particular Attention to When Using KD?
Baseline assessment of certain serum (lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D, and free and total carnitine) [41] and anthropometric (weight, height) parameters [5,33,53] are imperative to effectively see how values trend overtime with KD. This objective data collected longitudinally allows monitoring of metabolic and systemic side effects of KD to allow for cessation if need-be.
After deciding that KD is appropriate, the next step is to carefully review all standing orders in the patient’s chart to identify potential sources of hidden carbohydrates and replace with alternatives. Guidance by the dietary/nutrition team as well as an ICU pharmacist are recommended to improve success with achieving and maintaining ketosis. If possible, a nutritionist with knowledge and experience with managing a KD is preferred, which may necessitate involving the pediatric nutrition team.
In the critical care setting, nutrition is often dictated by the critical care team via administration of formula tube feeding, and patient compliance is not a key factor for achieving ketosis. Route of administration does impact ketosis as suspension or elixir medications, [53] the preferred formulations via percutaneous gastrostomies (PEG) or other enteral routes, must be replaced by alternative formulations with lower carbohydrate content [7]. Additionally, dextrose-free diluents [52] must be used whenever able in intravenous drug formulations. Unavoidable carbohydrates can be balanced with a calculated dose of fat in the form of MCT oil or a commercially available emulsified oil (provided that this addition coincides with caloric and macronutrient percentages discussed later). Additionally, this puts the patient at an increased risk for gastrointestinal complications such as steatorrhea, emesis and reflux.
14. Ketosis Maintenance and Surveillance
Inducing ketosis is only the first step in tackling SE. While a ketotic state is commonly defined as beta-hydroxybutyrate >2 mmol/L [30], similarly to antiseizure drugs, some individuals require higher level of ketosis (or antiseizure drugs) to achieve optimal seizure control. Thus, individual thresholds for optimal ketotic state may vary. In the presented case, the best therapeutic effect was noted with beta-hydroxybutyrate >3.5. Maintaining ketosis above a certain therapeutic level proves to be difficult, particularly when higher targets are required such as >3 mmol/L beta-hydroxybutyrate [7]. For example, Cobo’s case series illustrated that children with SRSE can have sudden, unexplained drops in beta-hydroxybutyrate levels.
After KD was stopped on HD 73 due to poor nutritional status, KD was reinitiated on HD 106 as the patient was no longer on bolus medications with high carbohydrate content. Ketosis was achieved rapidly over two days, with a beta-hydroxybutyrate of 2.34 mmol/L target once the goal of 6:1 ratio 18 kcal/kg was reached. The rapid achievement of ketotic state likely resulted from several days of fasting prior to its initiation in the setting of percutaneous gastrostomy placement and enterocutaneous fistula repair. The patient remained in ketosis, with beta-hydroxybutyrate levels fluctuating between 1.93–5.32 mmol/L, during which time seizures were best controlled when beta-hydroxybutyrate levels were >3.5 mmol/L.
Constant evaluation and re-evaluation of patient intake, including intravenous fluids, must be conducted. It is imperative to remove all common exogenous carbohydrates including glycerin, maltodextrin, propylene glycol, dextrose, fructose, glucose, lactose, sucrose, corn syrup, sugar alcohols and starches [52]. Appropriate alternatives include normal saline, balanced crystalloid or lactated Ringer’s solution.
15. Question: What Natural Physiologic Mechanisms Must Be Accounted for When Attempting to Achieve/Maintain Ketosis?
In addition to exogenous carbohydrate management, the intensivist must not overlook endogenous perturbations of glucose homeostasis. Commonly measured anywhere from every four [54] to eight hours after initiation of KD [7], fluctuations are commonly seen in the pediatric population as the clinician attempts to titrate to a glucose target level of 60–79 mg/dL [7]. While the lower limit of 40 mg/dL is referenced in the Academy of Nutrition and Dietetics Practice Paper, the clinicians at Yale New Haven Hospital use a slightly higher limit of 50 mg/dL when evaluating for KD initiation. Ketosis can be threatened by endogenous gluconeogenesis occurring during infection or injury [55]. The topic of glucose perturbations brings up the discussion of whether the use of glucocorticoids concurrently with KD hinders the diet’s efficacy. Among children with epilepsy being treated with KD, there have been reports of glucocorticoid use (even inhaled) being associated with seizure return, elevated glucose and ketosis hindrance [56]. More studies are needed to examine the relationships of KD and glucocorticoid use in the setting of SE/RSE.
16. KD and Supplements
Question: What Supplements may Be Warranted when Starting a Ketogenic Diet?
The KD’s inherent shift into fatty acid beta-oxidation predisposes to metabolic acidosis, which can be further compounded if individuals are fasting to achieve ketosis [36]. For these reasons, adequate bicarbonate levels (commonly >17 mmol/L) [7] should be ensured with concomitant sodium bicarbonate [5] and/or potassium citrate supplementation [7].
Beta-oxidation in the mitochondria is reliant on the adequate transport of long-chain fatty acids across the mitochondrial membrane via carnitine [36,53]. Carnitine supplementation is recommended when levels are low (<30 μmol/L) or if the patient is symptomatic, defined by lethargy, weakness and GI symptoms, which are often difficult to assess in a comatose patient [7,36,53]. Carnitine supplementation remains controversial, as levels poorly correlate with tissue stores and symptoms of carnitine deficiency may be difficult to identify in comatose patients [53].
Lastly, it is recommended that a low carbohydrate multivitamin, calcium carbonate and Vitamin D be added [34,36] via nasogastric/gastric tube (NG/G-tube). Most commercially available ketogenic formulas have the recommended daily allowance of these substances. Children with epilepsy have hypovitaminosis D (50%) and are at risk for osteoporosis [36,53]. Phosphorous, [53] administered separately to avoid calcium chelation, is a recommended supplement for its role in bone homeostasis. Lastly, it is our recommendation to supplement either lite salt or table salt for patients that have hyponatremia despite administration of sodium containing intravenous fluids.
17. Termination of Ketotic Therapy
Question: Once Anesthetics Have Been Weaned and/or Seizure Activity Has Improved, How Should KD Be Weaned?
Reasons for diet discontinuation include lack of response, development of complications and need for optimization of nutritional status. There are no clear guidelines to define a clear response to KD, as diseases and patient populations are very heterogeneous, and a clear absolute seizure cessation effect may not be seen. In some cases, allowing for anesthetic wean or antiseizure regimen simplification may be considered successful results. It is our recommendation that before considering therapeutic failure, higher ketotic levels should be pursued if the patient is able to tolerate a more aggressive titration of the KD, as patients, such as our patient, may respond to higher beta-hydroxybutyrate levels.
Like any antiseizure therapy, it is generally recommended to wean the KD diet gradually due to the historical thought that abrupt withdrawal of ketosis can precipitate recurrence of seizures or SE. Abrupt withdrawal of KD is recommended for emergencies only. Thus, gradually reducing the ratio of grams of fats:protein + carbohydrates is recommended (i.e., 4:1 to 3:1 to 2:1) [36]. Despite there being a common notion that overzealous weaning of KD can precipitate previously suppressed seizure activity, a study of over 183 children showed no significant difference in the incidence of seizures worsening between discontinuation/weaning rates (i.e., <1 week vs. 1–6 weeks vs. >6 weeks) [57]. However, there was an increase in seizure activity with faster weaning schedules among a particular cohort: children who had higher percentage (55–90%) of seizure reduction while on the KD. Additionally, among children who successfully stopped KD after seizure cessation, 42% of them were unable to achieve symptom improvement with either ASD or reinitiating of KD upon seizure relapse [58].
We recommend that the clinician use the KD’s treatment success as well as clinical judgement in adopting an individualized weaning schedule. Beginning on HD 194, our patient was weaned from the KD over five days by decreasing the ketogenic formula by 20% every 24 h and replacing it with a traditional critical care formula. Supplemental MCT oil was decreased at the beginning of the weaning process. No complications arose during this transition. Once able to tolerate oral nutrition, the patient will have the autonomy to determine whether to continue KD and contingency plans, such as offering a less strict KD therapy (modified Atkins diet, modified KD), which may be a reasonable alternative.
18. Anticipating and Managing Complications
Question: What Are Some Potential Complications of KD?
Complications of KD are not uncommon and may result in discontinuation of the diet. In the pediatric literature, 30 [6] to 38% discontinuation rates [59] are described due to inability to tolerate the diet or due to complications. These complications include metabolic derangements like dyslipidemia and hyperuricemia, gastrointestinal symptoms, renal stones, osteopenia and cardiac problems like QT prolongation and cardiomyopathy [36,59]. An uncommon yet reported complication is protein-losing enteropathy [60], and while this can be corrected for by cessation of KD, the likely consequence is an increase in seizures. Like osteoporosis and Vitamin D alterations, which may not be relevant in the setting of acute KD administration for RSE, these complications are less relevant in the setting of short-term KD. Rather, more relevant complications to be aware of include dehydration, hyponatremia, metabolic acidosis, hypoglycemia, gastroparesis and nausea/vomiting [5,59].
Aside from poor wound healing and critical illness myopathy, our NORSE patient tolerated KD well and was discharged after 218 days in the hospital. Additional longitudinal studies are needed to examine long-term sequelae of a high fat diet in the context of adults with SE. Future research may focus on complication rates specifically associated with acute administration of KD for adult patients with RSE/SRSE in the neurological ICU setting, as well as cessation upon symptom improvement. Our patient’s neurological examination at discharge was significant for spontaneous eye opening, orientated x 2, minimally talkative with soft but clear speech. She was able to follow simple commands like closing her eyes and wiggle her toes. Strength was 3/5 proximal upper extremity with 2/5 in distal upper and proximal lower extremity. The patient was readmitted three weeks later for cardiac arrest, with subsequent reemergence of status epilepticus. Despite EEG improvement on restarting KD, the patient was eventually transitioned to comfort measures only.
19. Future of KD in Adult SE/RSE/SRSE/NORSE
While the utility of KD in adult populations is certainly promising for the management of RSE and SRSE, there remain several gaps, including a lack of standardized treatment approach, lack of randomized, double-blind controlled studies and hidden carbohydrate sources, which may impair production of ketone bodies. These inconspicuous carbohydrates are found in commonly administered medications for SE including benzodiazepines, antibiotics, electrolyte repletion formulations and even solutions used for oral care. This review offers a brief outline of treatment strategies for KD use in adults and a systematic approach for successfully achieving, maintaining and eliminating ketosis.
Acknowledgments
Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
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Author Contributions
Conceptualization, C.B.M., J.B.K., K.O.; Methodology, C.B.M., J.B.K., K.O.; Data Curation, C.B.M., M.C.C., L.J.H., K.O.; Writing—Original Draft Preparation, J.B.K..; Writing—Review & Editing, I.N., R.B., N.A.D., E.J.G., C.B.M.; Visualization, J.B.K., C.B.M., Supervision, C.B.M.; Project Administration, C.B.M.; Software, NA; Validation, NA; Formal analysis, NA; Investigation, NA; Resources, NA; Funding, NA. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
This report is a case study, therefore not meeting the Common Rule definition of research as it is not designed to develop generalizable knowledge and did not required ethical approval.
Informed Consent Statement
Given the retrospective nature of this report, the fatal outcome, and the lack of identifiable information, family was not contacted to obtain informed consent.
Conflicts of Interest
The authors declare no conflict of interest. Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
Appendix A
Briviact (brivaracetam injection) [package insert]. Smyrna, G. and I.R.M. UCB.
Cerebyx (fosphenytoin sodium injection) [package insert]. New York, N. and I.R.F. Pfizer.
Propofol injectable emulsion [package insert]. Lake Forest, I. and I.R.M. Hospira.
Ketalar (ketamine hydrochloride injection) [package Insert]. Chestnut Ridge, N., P. Pharmaceutical, and R.A. 2020.
Vimpat (lacosamide injection) [package insert]. Smyrna, G. and I.R.N. UCB.
Midazolam hydrochloride injection [package insert]. Lake Forest, I. and I.R. Hospira.
Thiopental sodium injection [package insert]. Galashiels, U. and L.R.O. Kyowa Kirin.
Valproate sodium injection [package insert]. Eatontown, N. and W.-W.P.C.R.M. 2019.
Sulfamethoxazole and trimethoprim injection [package insert]. Morgantown, W. and M.I.L.R.D. 2020.
Vancomycin hydrochloride for injection [package insert]. Rockford, I. and M.I.L.R.J. 2018.
Carbatrol (carbamazepine extended-release tablet) [package insert]. Lexington, M. and I.R.N. Takeda Pharmaceuticals America.
Levetiracetam immediate-release tablet [package insert]. Chestnut Ridge, N. and P.P.R.S. 2020.
Metamucil (psyllium husk powder) [product information]. Cincinnati, O. and P.G.R.D. 2019.
Divalproex sodium extended-release tablets [package insert]. Bridgewater, N. and A.P.L.R.A. 2020.
Peridex (chlorhexidine gluconate 0.12%) [package insert]. 3M Canada Company Dental Products. 2007.
Figure 1 Drug Interference with achievement of ketosis. Seizure Activity: On HD 14–16, seizure burden was 90% nonconvulsive status epilepticus (NCSE) and decreased to 10–15% by hospital day (HD) 23–24. From HD 30–39, % ictal ranged from 5–20% with HD 40 showing <1% ictal. % Ictal increased briefly during HD 41–47 with an average of 15% ictal but decreased to <1% by HD 48/49. % Ictal remained in the 10–20% range until HD 57 with % ictal < 1. From HD 58–72 % ictal ranged from 5–20% until % ictal <5 by HD 72.
jcm-10-00881-t001_Table 1Table 1 Summary work-up for New-Onset Refractory Status Epilepticus (NORSE) patient.
Categories Serum CSF Imaging Pathology
Infectious: Influenza A/B, H1N1, RPR, HIV, cat scratch panel, tick borne panel, Mycoplasma pneumonia, B Henselae, B quintana (all negative) West Nile Virus, Enterovirus, Bacterial culture, HSV, VZV, Lyme disease, fungal culture, HHV6, EBV, Mycoplasma pneumoniae (all negative)
Inflammatory: ANA, dsDNA, SSA, SSB, SCL 70, CRP, ESR, TPO antibody, thyroglobulin antibody, complements (C3, C4, CH50), ANCA, B2 glycoprotein, anticardiolipin, Antiribosomal P protein Ab, ACE, smooth muscle antibody, skeletal muscle antibody AMPA-R Ab, CASPR2 Ab, DPPX Ab, GABA-B-R Ab, GAD 65, GFAP, LGI1-IgG, mGluR1 Ab, NMDA R Ab
Paraneoplastic: GAD 65, NMDA, voltage gated potassium channel antibody, flow cytometry AChR ganglionic neuronal Ab, Amphiphysin Ab, Antiglial nuclear Ab, Antineuronal nuclear Ab, CRMP-5, Neuronal (V-G) K+ channel Ab, N-Type Calcium channel ab, P/Q type calcium channel Ab, Purkinje cell cytoplasmic Ab, Striational Ab (all negative)
Metabolic: TSH (0.22), Free T4 (1.7 ng/dL), Ammonia (47, 33, 37 µL/dL), serum and urine toxicology (negative)
MRI brain w/wo contrast: restricted diffusion and hyperintense FLAIR signal in the bilateral hippocampi Benign ovarian cyst
CT Chest/abdomen/pelvis: no evidence of ovarian teratoma or other malignancy No malignant cells in CSF
US pelvis: tiny 3–4 mm echogenic focus on the left ovary which may represent a small calcification, however, a tiny teratoma cannot be excluded
MRI pelvis: no evidence of ovarian teratoma
Work-up recommendations from Table 1 from Sculier C, Gaspard N. New onset refractory status epilepticus (NORSE). Seizure. 2019 May; 68:72–78. doi: 10.1016/j.seizure.2018.09.018. Epub 2018 Sep 29. PMID: 30482654. [18]. Influenza A/B: negative; H1N1: negative; Smooth and skeletal muscle antibody: negative; RPR: rapid plasma reagent—negative; ANA: antinuclear antibody—1:2560 titer; dsDNA: double-strand DNA—positive, 38.4 IU/mL; SSA: Sjögren’s Syndrome A—greater than 8; SSB: Sjögren’s Syndrome B—negative; SCL 70: Scleroderma (antitopoisomerase)—negative; Antiribosomal P protein—negative; CRP: C-reactive protein—54 mg/L; ESR: erythrocyte sedimentation rate—51 mm/h; C3/C4/CH50: within normal limits; B2 glycoprotein—negative; Anticardiolipin—negative; TPO: thyroperoxidase antibody—negative; thyroglobulin antibody—negative; ANCA: antineutrophil cytoplasmic antibody—negative; ACE: angiotensin converting enzyme—within normal limits; GAD 65: Glutamic acid decarboxylase—negative; NMDA: N-methyl-D-Aspartate receptor antibody—negative; AMPA: α-amino-3-hydroxy-5-methyl-4 -isoxazolepropionic acid receptor- antibody negative; TSH: thyroid stimulating hormone—within normal limits; HIV: Human immunodeficiency virus—negative; Lyme disease—negative; West Nile Virus—negative; Enterovirus- negative; Bacterial and fungal culture—negative; HSV: Herpes Simplex Virus—negative; VZV: Varicella Zoster Virus—negative; HHV6: Human Herpes Virus 6—negative; EBV: Epstein Barr Virus—negative; GFAP: Glial Fibrillary Acidic Protein—negative; LGI1: Leucine-rich glioma-inactivated—negative; CASPR2: Contactin-associated protein-like 2—negative; DPPX: dipeptidyl-peptidase-like protein 6—negative; GABA: gamma-aminobutyric acid—negative; mGlu1: metabotropic glutamate receptor 1—negative; CRMP-5: CV2/collapsin response mediator protein—negative; Voltage gated potassium channel—negative.
jcm-10-00881-t002_Table 2Table 2 Common antiseizure medications, medications utilized in hospitalized patients and associated carbohydrate, fat, and alcohol content.
Intravenous Product (General Product Concentration)
Carbohydrate Excipient and Amount Per Vial
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Brivaracetam (10 mg/mL) – – – –
Diazepam (5 mg/mL) [41] Propylene glycol: 414 mg 828 mg CHO/10 mg – 79 mg
Famotidine (10 mg/mL) [41] Mannitol: 20 mg 40 mg CHO/40 mg – –
Fosphenytoin [42] – – – –
Lorazepam (2 mg/mL) [42] Propylene glycol: 753 mg – – –
Pentobarbital (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Phenobarbital (130 mg/mL) [41] Propylene glycol: 702 mg – – 79 mg
Phenytoin (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Propofol (10 mg/mL) [41] Glycerol: 22.5 mg/mL 450 mg CHO/h
(20 mL/h) Soybean oil: 100 mg/mL Benzyl alcohol *
Egg Lecithin: 12 mg/mL
Lipid: 100 mg/mL
(1.1 kcal/mL)
Ketamine (multiple) – – – –
Lacosamide (multiple) – – – –
Midazolam (multiple) – – – Benzyl alcohol †
Thiopental (25 mg/mL) – – – –
Valproate (20 mg/mL) – – – –
Trimethoprim-sulfamethoxazole (Bactrim®) diluted in Dextrose 5% W 100 mL per 80–400 mg TMP-SMX Dextrose: 5 g/100 ml Up to 20 g CHO per dose – –
Vancomycin (Vancocin®) diluted in Dextrose 5% W per 1 g/250 mL solution Dextrose: 5 g/100 ml Up to 2 g CHO per dose – –
Enteral Product § (General Product Strength)
Carbohydrate Excipient and Amount Per Unit
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Carbamazepine (extended-release tablet) Lactose monohydrate ‡
Microcrystalline cellulose ‡ – – –
Clobazam (10 mg tablet) [43] 105.3 mg/tablet ≈100 mg/10 mg – –
Clonazepam (0.5 mg tablet) [43] 143.5 mg/tablet ≈2800 mg/10 mg – –
Levetiracetam (immediate release tablet) Croscarmellose sodium ‡
Polyethylene glycol 3350 ‡
Polyethylene glycol 6000 ‡ – – Polyvinyl alcohol
Psyllium (Metamucil) packet 9 g CHO/tablespoon 27 g CHO/day (TID) – –
Divalproex sodium (extended-release tablet) Hypromelloses ‡
Lactose monohydrate ‡
Polyethylene glycol ‡
Propylene glycol ‡
Macrogol ‡
Microcrystalline cellulose ‡ – – n-Butyl alcohol
Isopropyl alcohol
Polyvinyl alcohol
See Appendix A for package inserts. * Present at 1.5 mg/mL in all vial sizes (0.15% w/v). Avoid use in pediatric populations due to benzyl alcohol content. † Present at 10 mg/mL in all vial sizes (1% w/v), except preservative-free formulations. Avoid use in pediatric populations due to benzyl alcohol content. ‡ Unknown amount of relative excipient may affect ketosis but is likely clinically insignificant. § Solution and suspension formulations should be avoided if possible as they usually contain sugars that will affect ketosis.
jcm-10-00881-t003_Table 3Table 3 Ketogenic Diet checklist for Status Epilepticus.
Pearls to Consider for Starting and Maintaining a Ketogenic Diet (KD)
I. KD initiation
○ Check fasting lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D serum levels
○ Record baseline weight and height
○ Continuous video EEG
○ Dietitian/nutrition consult (consider pediatric nutritionist)
○ Stop current enteral formula
○ Reduce carbohydrate content in medications and parenteral fluids with pharmacy input
○ Active communication with nursing/pharmacy, EMR warnings, and signs in room are crucial to avoid medication/IV-containing carbohydrates
○ Begin KD (e.g., KetoCal/MCT oil)
○ Include multivitamin injection, Vit. D and calcium supplementation via nasogastric tube/gastric tube
○ Change any oral agents from liquid formulation to crushed tablet formulation
II. KD maintenance
○ Remove all common carbohydrate excipients in intravenous fluids, including:
○ Glycerin
○ Maltodextrin
○ Propylene glycol
○ Sugars (dextrose, fructose, glucose, lactose, sucrose, corn syrup)
○ Sugar alcohols (glycerol, mannitol, sorbitol)
○ Starches
○
KD can be challenged via coadministration of other meds & IVs!
III. Pitfalls to consider:
○ Contraindications: unstable metabolic derangements, hemodynamic instability, coagulopathy/bleeding diathesis, pancreatitis, liver failure, severe hyperlipidemia, ileus, pregnancy, known fatty acid oxidation disorder or pyruvate carboxylase deficiency
○
Propofol infusions cannot be given within 24 h before starting a KD!
Adapted & modified from Table 3 from Thakur KT, Probasco JC, Hocker SE, et al. Neurology. 2014 Feb 25; 82(8): 665–670. [4]. | UNKNOWN DOSE | DrugDosageText | CC BY | 33671485 | 19,466,490 | 2021-02-22 |
What was the dosage of drug 'LORAZEPAM'? | Pearls and Pitfalls of Introducing Ketogenic Diet in Adult Status Epilepticus: A Practical Guide for the Intensivist.
Background: Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of a ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and effective. Methods: We describe our experience, including the challenges of achieving and maintaining ketosis, in an adult with new onset refractory status epilepticus (NORSE). Case Vignette: A previously healthy 29-year-old woman was admitted with cryptogenic NORSE following a febrile illness; course was complicated by prolonged super-refractory SE. A comprehensive work-up was notable only for mild cerebral spinal fluid (CSF) pleocytosis, elevated nonspecific serum inflammatory markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI). Repeat CSF testing was normal and serial MRIs demonstrated resolution of edema and diffusion restriction with progressive hippocampal and diffuse atrophy. She required prolonged therapeutic coma with high anesthetic infusion rates, 16 antiseizure drug (ASD) trials, empiric immunosuppression and partial bilateral oophorectomy. Enteral ketogenic formula was started on hospital day 28. However, sustained beta-hydroxybutyrate levels >2 mmol/L were only achieved 37 days later following a comprehensive adjustment of the care plan. KD was challenging to maintain in the intensive care unit (ICU) and was discontinued due to poor nutritional state and pressure ulcers. KD was restarted again in a non-ICU unit facilitating ASD tapering without re-emergence of SE. Discussion: There are inconspicuous carbohydrates in commonly administered medications for SE including antibiotics, electrolyte repletion formulations, different preparations of the same drug (i.e., parenteral, tablet, or suspension) and even solutions used for oral care-all challenging the use of KD in the hospitalized patient. Tailoring comprehensive care and awareness of possible complications of KD are important for the successful implementation and maintenance of ketosis.
1. Introduction
Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and potentially effective [1,2,3,4,5]. Most often used in childhood epilepsies, KD has emerged as a potential adjunctive treatment for pediatric SE [6,7]. We describe our experience with an adult with new onset refractory status epilepticus (NORSE) focusing on the unexpected challenge of achieving and maintaining ketosis. Practical advice, and a comprehensive review of factors potentially jeopardizing ketosis commonly encountered in the critical care setting and alternatives are provided.
2. Presentation
A previously healthy 29-year-old woman was admitted to another institution with new onset refractory status epilepticus (NORSE) following a febrile illness with a course complicated by prolonged super-refractory SE. Three days prior to presentation she developed fever, headache, emesis and fatigue in the setting of being in contact with her child with an upper respiratory tract infection. On the morning of admission, her friend attempted to awaken her for work and found her unresponsive and convulsing. In the emergency department, she was lethargic and mumbling incoherently. During her initial evaluation she had a witnessed 45-s bilateral tonic-clonic seizure that was aborted with 2 mg lorazepam intravenously. Head computed tomography was unremarkable and initial cerebrospinal fluid (CSF) analysis showed a mononuclear pleocytosis (2 RBC, 41 nucleated cells (57% mononuclear cells), glucose 93, protein 54)). A one-hour electroencephalogram (EEG) showed diffuse delta activity admixed with sleep spindles and K complexes without epileptiform discharges. She was monitored in the step-down unit and treated with levetiracetam and acyclovir. On hospital day two, she was somnolent but arousable to voice; she was able to follow simple midline commands, state her name and the current president, but was disoriented to time. She was noted to have twitching of her face, but no EEG was done at that time. By hospital day three, she began experiencing brief convulsive seizures which were aborted with intravenous lorazepam and always associated with recovery of consciousness. At that point, phenytoin (1 g loading dose, maintenance at 100 mg q8h) was added to her antiseizure drug (ASD) regimen. On hospital day four, she had multiple convulsive seizures without return to baseline, complicated by acute hypoxic respiratory failure requiring intubation. She was transferred to the intensive care unit (ICU) where she was started on propofol, and valproic acid (20 mg/kg loading dose, maintenance at 750 mg Q8H) was added. Routine EEG captured multiple discrete right frontal and centrotemporal onset seizures correlating with episodes of face twitching. She was started on pentobarbital infusion (5 mg/kg bolus, maintenance at 1 mg/kg per hour) and transferred to our center for continuous EEG monitoring.
3. Question: How Is Prolonged Seizure Activity Classified and What Are Potential Etiologies to Be Considered?
According to the most recent classification set by The International League Against Epilepsy, SE is a “condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures” [8]. While operational SE definitions based on time-domains vary according to seizure type, it is generally accepted that convulsive seizure activity lasting either greater than 5 min continuously, or two or more seizures during which the individual does not recover to baseline between seizures, represents SE [8]. Inhibitory gamma-aminobutyric acid (GABA) neurons located in the pars reticulata of the substantia nigra are key in seizure termination [9]. During status epilepticus, marked alteration of GABA metabolism occurs in this region and results in disinhibition of excitatory pathways: GABA synthesis slows down [10]. GABA turnover time increases up to three-fold, [10] and GABA receptors (originally located in the surface of the cell membrane) migrate to the intracellular space within minutes of ongoing seizure activity [11,12,13]. Prompt initiation of abortive therapies is key, as the internalization of GABA receptors contributes to refractoriness to treatment.
Emergent administration of parenteral benzodiazepine (e.g., up to 0.1 mg/kg of lorazepam) is considered the first-line therapy for SE [14]. If a patient fails to respond to a benzodiazepine and a second appropriately selected and dosed ASD at adequate doses, they are in refractory status epilepticus (RSE). It has been reported that one in five RSE patients go on to develop super-refractory status epilepticus (SRSE), defined as (1) ongoing seizures lasting 24 h or more after onset of anesthetic therapy (i.e., propofol) or (2) recurrence of SE upon reduction or withdrawal of therapeutic anesthetic coma [15]. The clinical presentation of RSE in patients without overt acute or remote brain injury, prior epilepsy, or acute toxic/metabolic explanation is consistent with New Onset Refractory Status Epilepticus—NORSE [16]. Febrile Infection-Related Epilepsy Syndrome (FIRES) is a subset of NORSE, in which a febrile infectious illness precedes SE onset by 1–14 days [14,15,16]. Thus, our patient qualified as having the syndrome of FIRES as well as NORSE. Further, clinical criteria for unequivocal electroencephalographic status epilepticus in patients without known epileptic encephalopathy has been established in the Salzburg consensus: (1) repeating epileptiform discharges occurring >2.5 Hz, or (2) repeating epileptiform discharges occurring ≤2.5 Hz or rhythmic delta/theta activity >0.5 Hz plus (a) electroclinical response (improvement) following intravenous ASD challenge, (b) subtle clinical correlate associated with pattern, or (c) typical temporal and spatial evolution of pattern [17].
Determining the underlying etiology of SE may seem a daunting task. However, its importance in achieving seizure cessation cannot be underestimated. Outcome following SE is dependent on the etiology of seizures. Further, appropriately recognizing the electroclinical classification of seizures (i.e., identifying the seizure semiology and its electrographic signature) may not only help selection of therapy but also identify potential etiologies [8]. Among NORSE patients, an etiology is found in up to 50% of cases [16]. Of those with an identifiable cause, the majority (37%) had an autoimmune cause (both nonparaneoplatic and paraneoplastic), while 8% had a probable infectious cause [16]. Thus, if an autoimmune etiology is diagnosed or clinically suspected, immune modulating therapies such as high-dose corticosteroids, intravenous immunoglobulin (IVIg) or plasma exchange therapy, followed by monoclonal antibodies and/or interleukin inhibitors, should be considered early in the course.
Our patient underwent a comprehensive work-up to determine the etiology of NORSE, as summarized on Table 1, which was notable only for mild CSF pleocytosis, elevated nonspecific inflammatory serum markers and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI).
4. Question: What Are the Initial Steps in the Therapeutic Algorithm for Status Epilepticus?
Benzodiazepines are the first-line treatment for SE [14,19] with slower-acting, less sedating parenteral ASDs being the second line (e.g., phenytoin, fosphenytoin, valproate and levetiracetam; and possibly lacosamide and phenobarbital). The Established Status Epilepticus Treatment Trial (ESETT) found no difference in efficacy between fosphenytoin (20 mgPE/kg), valproate (40 mg/kg) and levetiracetam (60 mg/kg) in children, adults and older adults; these ASDs were able to abort SE within an hour in nearly 50% of patients [20]. Once the second-line, or a combination of medications, fails to result in seizure cessation, continuous intravenous infusions of anesthetics (i.e., midazolam, pentobarbital, propofol, ketamine) are often recommended [14,19].
In patients with SE, anesthetic use is associated with longer hospital stay, but not in-hospital or 90-day mortality [21]. Amongst NORSE patients who receive anesthetics, the mortality is high. However, the use of anesthetics is not associated with poor outcome [16]. In 61 patients with RSE, those who underwent deep sedation (defined as either EEG showing burst suppression or isoelectric activity) had both poorer long-term prognosis and increased mortality [22]. Burst suppression on EEG is defined as intermittent alternating periods of low amplitudes (<10 uV for burst suppression; 10–20 uV for burst attenuation) interrupting a background, which may consist of waves of varying frequencies. Earlier attainment of burst suppression may allow for a more rapid anesthetic wean [23], and it is important to frequently monitor the EEG and titrate anesthetic dose as appropriate. The goal of anesthetic use in RSE is the resolution of epileptiform activity in order to avoid physiologic effects while the underlying cause is identified and treated [24,25].
In our case, 16 antiseizure drug trials in various combinations and high anesthetic infusion rates were attempted. RSE persisted despite 160 mg/h (2.5 mg/kg/h) of midazolam prompting the initiation of ketamine. Despite improved seizure burden following ketamine bolus (1.5 mg/kg), reemergence of SE occurred despite up-titration of ketamine to our maximum infusion rate (7.5 mg/kg/h). Her EEG responded to propofol and pentobarbital with long periods of suppression, although her background remained with abundant generalized periodic discharges (GPD) at 2.5–3 Hz, qualifying as ongoing electrographic SE. [17,26] Burst suppression was eventually achieved with pentobarbital at 3 mg/kg/h and propofol at 40 mcg/kg/min. However, due to re-emergence of 2 Hz GPDs along with breakthrough seizures on attempted wean, she remained in a medically induced coma for over three months.
5. Question: What Are Potential Rescue Therapeutic Approaches to the Management of Super-Refractory Status Epilepticus?
Refractory and super-refractory SE and their complications are associated with significant morbidity including death, neuronal damage and systemic complications like cardiomyopathy, ischemic bowel, pulmonary edema and renal failure [27]. This highlights the necessity for a prompt and aggressive treatment approach. In the setting of treatment failure, alternative treatment options include inhaled anesthetics, magnesium infusion, pyridoxine, hypothermia, electrical and magnetic stimulation, additional immunotherapy, enteral ASDs and the KD [28].
Given a high suspicion for an autoimmune process, our patient was treated with intravenous methylprednisolone (1 g daily for 5 days), IVIg, plasma exchange and cyclophosphamide. Serial MRIs demonstrated resolution of edema and diffusion restriction with gradually progressive atrophy, predominantly in the hippocampi, and repeat CSF analysis was normal. She underwent empiric bilateral partial oophorectomy for an echogenic focus in her left ovary and concern for possible occult microteratoma, possibly secondary to N-methyl-D-Aspartate (NMDA) encephalitis (NMDA CSF < 1:1 and serum < 1:10) [29].
6. Ketogenic Diet
Ketosis is commonly defined as sustained beta-hydroxybutyrate levels > 2 mmol/L [30] or a urinary acetoacetate level of >40 mg/dL [31]. There is evidence supporting the use of KD in children with autoimmune epilepsies, symptomatic epilepsy syndromes, pediatric refractory and super-refractory SE [6,32]. In a study of 10 children (age six months—16 years old) with refractory focal SE, initiation of a KD resulted in lower seizure burden (50% reduction in seizures for 70% of the cohort) and resolution of seizures in 20% [6]. In the minority of patients with less than 50% seizure reduction (n = 3), severe adverse events (pancreatitis or severe vomiting and hypoglycemia) prompted KD discontinuation. In another study of 12 children with fever induced refractory epileptic encephalopathy, KD was able to stop seizures within two days following ketonuria [32]. Nevertheless, the side effects of KD limit its widespread use, and successful ketosis must be attained for seizure control.
More recently, KD has been evaluated in adult patients; a systematic review of 38 adult patients with RSE or SRSE demonstrated that 82% were able to achieve SE cessation with KD [33]. There are several complex mechanisms for the efficacious effect of KD on reducing seizure activity, which result from reduction in glucose intake, ketone body production and alteration of the gut microbiome. The metabolic changes induced by KD alter the balance of excitatory and inhibitory neurotransmitters, lead to reductions in oxidative stress and systemic as well as neuroinflammation, and have further long-term effects on gene expression [3,34].
We sought KD as a rescue therapy after conventional treatments had failed.
7. Question: What Are Some Factors Should the Clinician Consider When Selecting and Initiating KD for Adults with SE?
Initiating KD Safely
Determining the optimal patient for whom to implement KD requires a comprehensive evaluation of the patient’s past medical history, comorbidities and current clinical status. As with all treatment strategies, particularly in the ICU setting, a thoughtful risk-benefit analysis is warranted. Inborn errors of metabolism are a contraindication to KD [35,36]. However, these conditions most often present in early childhood, and rarely in adults, so screening is not routinely obtained prior to KD initiation in adults [1,2]. Other contraindications of KD include unstable metabolic (mitochondrial enzyme deficiencies) conditions, liver failure, acute pancreatitis, pregnancy and an inability to tolerate enteral feeds [5]. Protocols typically avoid starting KD within 24 h of propofol infusions to avoid possibly fatal propofol infusion syndrome, characterized by metabolic acidosis, lipemia, rhabdomyolysis and myocardial failure [37].
8. Question: Should You Fast the Patient to Achieve Ketosis Quickly? If So, How Long and What Are Potential Consequences? If You Decide Not to Fast, Can Ketosis Still Be Achieved?
Variations in KD Protocols
Historically, KD implementation in the setting of childhood epilepsy included an initial fasting period ranging anywhere from 12 [7] to 48 [36,38] hours or more. Once satisfactory ketosis is achieved, ketogenic formulations or meals (typically 4:1 g of fat: carbohydrate + protein ratio) can then be titrated as tolerated until full caloric requirements are met. To avoid potential complications of a fasting period (e.g., dehydration, hypoglycemia), Kim et al. began KD without initial fasting and found equivalency in time to ketosis and seizure reduction in 41 children with intractable epilepsy compared to a retrospective control population of 83 children who fasted prior to KD initiation [39]. While rates of hypoglycemia were similar when compared to controls, there were reduced rates of dehydration and reduced length of hospital stay.
An alternative, yet equally efficacious approach for childhood epilepsy, does not involve initial fasting or limiting caloric intake. This protocol differs from others in the fact that there is a gradual increase from 1:1 to 2:1 until the goal 4:1 ratio is reached [38]. This gradual induction and establishment of ketosis in children diagnosed with intractable epilepsy showed an equal reduction in seizure activity yet decreased weight loss and episodes of hypoglycemia, acidosis and dehydration. Nevertheless, since time is a major factor in terms of avoiding neurologic and systemic consequences of SE, a more aggressive approach to KD initiation (i.e., fasting and/or more rapidly advancing to full calories as tolerated) may be warranted in this setting.
Individual patient characteristics including age, illness severity, duration of anesthetic use prior to diet initiation resulting in reduction in gastrointestinal motility, and diet complications, may not allow the luxury of initiating a preferred protocol with certain ketogenic ratio or at a faster rate. This was evident in Cobo’s pediatric SRSE study in which ratios were started as low as 0.75:1 in some instances, and ratios never exceeding 2:1 in some cases [7]. The need for higher protein intake (often in cases of poor wound healing, malnutrition and/or low basal resting energy expenditure) challenges the use of higher fat:protein + carbohydrate ratios, although this is more of a concern with chronic KD use rather than in the acute setting of RSE and SRSE. A possible way to maximize ketosis when using lower ratios (thus, higher protein intake) is the addition of medium-chain triglyceride oils as they yield greater amounts of ketones/kcal of energy than longer chain varieties [36].
We used these principles, most frequently used in the setting of childhood epilepsy, to initiate KD for our NORSE patient with the goal of achieving ketosis quickly. Our patient was initially started on KD on hospital day 28 (HD 28) with a goal of 5:1 ratio (KetoCal® 4:1 at 55 mL/h plus 33 mL medium-chain triglycerides (MCT) oil to balance carbohydrate intake from medications, documented as 51 g daily on HD 30). At this time, supplemental protein via PROsource® was discontinued to assist with achieving ketosis. On HD 35, beta-hydroxybutyrate (BHB) levels continued to show inadequate ketosis [Figure 1] prompting the increase to 6:1 with additional MCT Oil. Through HD 65, beta-hydroxybutyrate continued to fluctuate below the 2.0 goal. On HD 71, beta-hydroxybutyrate again dropped with the only documented potential carbohydrate source (at that time) being a milk and molasses enema administered by a care team to alleviate constipation. The decision was made to return to a higher carbohydrate-containing formula and refocus nutrition goals on wound healing. At this time, our patient was identified as meeting the criteria for severe malnutrition based on weight loss of >7.5% in three months and limited energy intake for greater than or equal to five days [40].
9. Question: What Factors Can Impede the Success of Achieving Ketosis, and thus Jeopardize the Utility of KD?
Despite initiating KD with complete enteral feeds on hospital day 28, our patient was only able to reach ketosis a significant 37 days later (Figure 1). After a comprehensive assessment of the care plan, the culprit was found: inconspicuous carbohydrate-containing medications, infusions and oral-care solutions routinely given in the setting of a neurological ICU (Table 2).
10. Hidden Carbohydrates Can Hinder Achievement of Ketosis
In our experience, the most likely medication-induced barriers to ketosis include sedatives, antiseizure drugs and antibiotics. Benzodiazepines are not created equally when it comes to hidden/nonobvious carbohydrate content. Diazepam (Valium® 5 mg/mL) and Lorazepam (Ativan® 2 mg/mL) have been shown to have 40% and 80% propylene glycol content, respectively, which equates to an overall carbohydrate content of 0.4 g/mL and 0.8 g/mL [42]. Intake of this carbohydrate content in patients with status epilepticus on KD may hinder achieving ketosis, but can also precipitate propylene glycol toxicity and associated anion-gap, metabolic acidosis [44].
While the carbohydrate load of each individual dose may be inconsequential, the cumulative dose given to patients in extended hospital stays may be significant. For example, initial administrations of injectable lorazepam, 2 mg every 6 h yields approximately 3 g of carbohydrate per day [44]. For context, this patient’s energy assessment used an ideal body weight of 64.5 kg, with daily caloric requirements calculated to total 2260 kcal/day (35 kcal/kg). Using KD at a 4:1 ratio (a common target for KD), the macronutrient breakdown is 226 g fat, 51.6 g protein, and 4.9 g carbohydrates. Thus, lorazepam would have contributed over half of the allotted daily carbohydrate load. Figure 1 shows several instances where lorazepam administration was associated with significant troughs in beta-hydroxybutyrate levels. When benzodiazepine infusions are warranted for refractory cases, our recommendation would be to consider midazolam as an alternative; midazolam does not have propylene glycol in its formulation, resulting in lower rates of anion-gap metabolic acidosis [45]. Regarding enteral administration of benzodiazepines, it is worth noting that clobazam (Onfi ®) and clonazepam (Klonopin®) contain 105 mg and 143.5 mg of carbohydrates (i.e., lactose, starch) per 10 mg/0.5 mg tablet, respectively [Table 2]. When selecting benzodiazepines for treatment of SE in patients treated with KD, it is important to evaluate the carbohydrate content for the selected benzodiazepine and the administration method. Generally, solutions and suspensions should be avoided due to high carbohydrate containing excipients.
Another class of widely used sedatives, often with the potential to inadvertently hinder beta-hydroxybutyrate levels, are the barbiturates, particularly pentobarbital (Nembutal® 50 mg/mL) and phenobarbital (Phenobarb® 130 mg/mL). Barbiturates are commonly used in RSE. However, they have a high propylene glycol content (pentobarbital 414 mg/50 mg vial, phenobarbital 702 mg/130 mg vial [42] amounting to an overall carbohydrate content of 2.9 g/h when pentobarbital is infused at a rate of 5 mg/kg/h for a 70 kg patient) [Table 2]. We suggest that ketamine (and midazolam, as discussed above) be considered as an alternative to pentobarbital in patients with status epilepticus on KD, given their lack of propylene glycol [46], This same concept can be applied for phenytoin (Dilantin® 50 mg/mL), which contains 40% propylene glycol [42] amounting to a carbohydrate content of 414 mg (plus an additional 79 mg of alcohol). These principles can be observed in Figure 1 where beta-hydroxybutyrate levels drop on HD 52, corresponding with a phenobarbital load (a disruption in feeds also occurred to administer phenytoin by mouth). We recommend that fosphenytoin be used instead to avoid propylene glycol excipients (Table 2). Similarly, on HD 56, beta-hydroxybutyrate dropped to 0.63 mmol/L with a medication review showing intravenous phenobarbital administered overnight. Lastly, another note of caution regarding anesthetic infusions: propofol contains 1.1 kcal/mL (mostly from fats), which provides approximately 528 kcal per day (presuming 20 mL/h). While this increased caloric load may aid in ketosis, its 450 mg of glycerol per 20 mL vial may hinder ketosis (Table 2).
11. Noncarbohydrate Related Hindrance of Ketosis
Among children with refractory epilepsy, concomitant lamotrigine use decreases KD’s efficacy in seizure reduction [47]. This may be explained by ketosis increasing the metabolism/inactivation of lamotrigine via glucosyltransferases, which ultimately results in increased glutamate release. Lastly, one must not forget that while medication use can influence KD, the inverse is also true. While most serum concentrations of ASD were not found to significantly change upon KD use, valproic acid levels have been shown to decrease [48]. Therefore, it is recommended to monitor valproic acid while using KD therapy.
12. Question: Aside from Sedative Agents, What Other Widely Used Agents in the Neurological ICU Can Hinder Ketosis?
12.1. Antimicrobials and Respective Diluents as Source of Carbohydrates
Various antibiotics that are used frequently in the neurological ICU [49,50] can hinder ketosis. Intravenous trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim®) requires reconstitution with dextrose 5% water and, similarly, vancomycin is often diluted in dextrose 5% water prior to intravenous administration (Table 2). Figure 1 (line graph) shows several instances in which administration of TMP-SMX and vancomycin were associated with troughs in beta-hydroxybutyrate levels.
12.2. Non “Medications” Contain Hidden Carbohydrates
Hidden carbohydrates are found in oral care solutions such as chlorhexidine, dietary supplements and fiber. Chlorhexidine 0.12% oral solution (PeridexTM), reported to be superior to toothbrushing at reducing early ventilator-associated pneumonia [51], contains glycerin and ethyl alcohol (see Appendix A), both carbohydrate-containing substances that can affect KD [52]. Oral fiber supplements, such as psyllium, have a significant carbohydrate load (e.g., 9 g/tablespoon) (Table 2). However, as fiber has a lower glycemic index compared to other carbohydrate-containing sources in the ICU setting, it may still be used in some instances to counteract constipation.
12.3. Comprehensive Approach to Implementing KD in Adult SE
Adopting a systematic approach is key for the successful implementation and maintenance of a ketotic state. A checklist is provided in Table 3 with a summary of the suggested steps for successful KD initiation [4].
13. Question: What Laboratory Values Should the Intensivist Pay Particular Attention to When Using KD?
Baseline assessment of certain serum (lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D, and free and total carnitine) [41] and anthropometric (weight, height) parameters [5,33,53] are imperative to effectively see how values trend overtime with KD. This objective data collected longitudinally allows monitoring of metabolic and systemic side effects of KD to allow for cessation if need-be.
After deciding that KD is appropriate, the next step is to carefully review all standing orders in the patient’s chart to identify potential sources of hidden carbohydrates and replace with alternatives. Guidance by the dietary/nutrition team as well as an ICU pharmacist are recommended to improve success with achieving and maintaining ketosis. If possible, a nutritionist with knowledge and experience with managing a KD is preferred, which may necessitate involving the pediatric nutrition team.
In the critical care setting, nutrition is often dictated by the critical care team via administration of formula tube feeding, and patient compliance is not a key factor for achieving ketosis. Route of administration does impact ketosis as suspension or elixir medications, [53] the preferred formulations via percutaneous gastrostomies (PEG) or other enteral routes, must be replaced by alternative formulations with lower carbohydrate content [7]. Additionally, dextrose-free diluents [52] must be used whenever able in intravenous drug formulations. Unavoidable carbohydrates can be balanced with a calculated dose of fat in the form of MCT oil or a commercially available emulsified oil (provided that this addition coincides with caloric and macronutrient percentages discussed later). Additionally, this puts the patient at an increased risk for gastrointestinal complications such as steatorrhea, emesis and reflux.
14. Ketosis Maintenance and Surveillance
Inducing ketosis is only the first step in tackling SE. While a ketotic state is commonly defined as beta-hydroxybutyrate >2 mmol/L [30], similarly to antiseizure drugs, some individuals require higher level of ketosis (or antiseizure drugs) to achieve optimal seizure control. Thus, individual thresholds for optimal ketotic state may vary. In the presented case, the best therapeutic effect was noted with beta-hydroxybutyrate >3.5. Maintaining ketosis above a certain therapeutic level proves to be difficult, particularly when higher targets are required such as >3 mmol/L beta-hydroxybutyrate [7]. For example, Cobo’s case series illustrated that children with SRSE can have sudden, unexplained drops in beta-hydroxybutyrate levels.
After KD was stopped on HD 73 due to poor nutritional status, KD was reinitiated on HD 106 as the patient was no longer on bolus medications with high carbohydrate content. Ketosis was achieved rapidly over two days, with a beta-hydroxybutyrate of 2.34 mmol/L target once the goal of 6:1 ratio 18 kcal/kg was reached. The rapid achievement of ketotic state likely resulted from several days of fasting prior to its initiation in the setting of percutaneous gastrostomy placement and enterocutaneous fistula repair. The patient remained in ketosis, with beta-hydroxybutyrate levels fluctuating between 1.93–5.32 mmol/L, during which time seizures were best controlled when beta-hydroxybutyrate levels were >3.5 mmol/L.
Constant evaluation and re-evaluation of patient intake, including intravenous fluids, must be conducted. It is imperative to remove all common exogenous carbohydrates including glycerin, maltodextrin, propylene glycol, dextrose, fructose, glucose, lactose, sucrose, corn syrup, sugar alcohols and starches [52]. Appropriate alternatives include normal saline, balanced crystalloid or lactated Ringer’s solution.
15. Question: What Natural Physiologic Mechanisms Must Be Accounted for When Attempting to Achieve/Maintain Ketosis?
In addition to exogenous carbohydrate management, the intensivist must not overlook endogenous perturbations of glucose homeostasis. Commonly measured anywhere from every four [54] to eight hours after initiation of KD [7], fluctuations are commonly seen in the pediatric population as the clinician attempts to titrate to a glucose target level of 60–79 mg/dL [7]. While the lower limit of 40 mg/dL is referenced in the Academy of Nutrition and Dietetics Practice Paper, the clinicians at Yale New Haven Hospital use a slightly higher limit of 50 mg/dL when evaluating for KD initiation. Ketosis can be threatened by endogenous gluconeogenesis occurring during infection or injury [55]. The topic of glucose perturbations brings up the discussion of whether the use of glucocorticoids concurrently with KD hinders the diet’s efficacy. Among children with epilepsy being treated with KD, there have been reports of glucocorticoid use (even inhaled) being associated with seizure return, elevated glucose and ketosis hindrance [56]. More studies are needed to examine the relationships of KD and glucocorticoid use in the setting of SE/RSE.
16. KD and Supplements
Question: What Supplements may Be Warranted when Starting a Ketogenic Diet?
The KD’s inherent shift into fatty acid beta-oxidation predisposes to metabolic acidosis, which can be further compounded if individuals are fasting to achieve ketosis [36]. For these reasons, adequate bicarbonate levels (commonly >17 mmol/L) [7] should be ensured with concomitant sodium bicarbonate [5] and/or potassium citrate supplementation [7].
Beta-oxidation in the mitochondria is reliant on the adequate transport of long-chain fatty acids across the mitochondrial membrane via carnitine [36,53]. Carnitine supplementation is recommended when levels are low (<30 μmol/L) or if the patient is symptomatic, defined by lethargy, weakness and GI symptoms, which are often difficult to assess in a comatose patient [7,36,53]. Carnitine supplementation remains controversial, as levels poorly correlate with tissue stores and symptoms of carnitine deficiency may be difficult to identify in comatose patients [53].
Lastly, it is recommended that a low carbohydrate multivitamin, calcium carbonate and Vitamin D be added [34,36] via nasogastric/gastric tube (NG/G-tube). Most commercially available ketogenic formulas have the recommended daily allowance of these substances. Children with epilepsy have hypovitaminosis D (50%) and are at risk for osteoporosis [36,53]. Phosphorous, [53] administered separately to avoid calcium chelation, is a recommended supplement for its role in bone homeostasis. Lastly, it is our recommendation to supplement either lite salt or table salt for patients that have hyponatremia despite administration of sodium containing intravenous fluids.
17. Termination of Ketotic Therapy
Question: Once Anesthetics Have Been Weaned and/or Seizure Activity Has Improved, How Should KD Be Weaned?
Reasons for diet discontinuation include lack of response, development of complications and need for optimization of nutritional status. There are no clear guidelines to define a clear response to KD, as diseases and patient populations are very heterogeneous, and a clear absolute seizure cessation effect may not be seen. In some cases, allowing for anesthetic wean or antiseizure regimen simplification may be considered successful results. It is our recommendation that before considering therapeutic failure, higher ketotic levels should be pursued if the patient is able to tolerate a more aggressive titration of the KD, as patients, such as our patient, may respond to higher beta-hydroxybutyrate levels.
Like any antiseizure therapy, it is generally recommended to wean the KD diet gradually due to the historical thought that abrupt withdrawal of ketosis can precipitate recurrence of seizures or SE. Abrupt withdrawal of KD is recommended for emergencies only. Thus, gradually reducing the ratio of grams of fats:protein + carbohydrates is recommended (i.e., 4:1 to 3:1 to 2:1) [36]. Despite there being a common notion that overzealous weaning of KD can precipitate previously suppressed seizure activity, a study of over 183 children showed no significant difference in the incidence of seizures worsening between discontinuation/weaning rates (i.e., <1 week vs. 1–6 weeks vs. >6 weeks) [57]. However, there was an increase in seizure activity with faster weaning schedules among a particular cohort: children who had higher percentage (55–90%) of seizure reduction while on the KD. Additionally, among children who successfully stopped KD after seizure cessation, 42% of them were unable to achieve symptom improvement with either ASD or reinitiating of KD upon seizure relapse [58].
We recommend that the clinician use the KD’s treatment success as well as clinical judgement in adopting an individualized weaning schedule. Beginning on HD 194, our patient was weaned from the KD over five days by decreasing the ketogenic formula by 20% every 24 h and replacing it with a traditional critical care formula. Supplemental MCT oil was decreased at the beginning of the weaning process. No complications arose during this transition. Once able to tolerate oral nutrition, the patient will have the autonomy to determine whether to continue KD and contingency plans, such as offering a less strict KD therapy (modified Atkins diet, modified KD), which may be a reasonable alternative.
18. Anticipating and Managing Complications
Question: What Are Some Potential Complications of KD?
Complications of KD are not uncommon and may result in discontinuation of the diet. In the pediatric literature, 30 [6] to 38% discontinuation rates [59] are described due to inability to tolerate the diet or due to complications. These complications include metabolic derangements like dyslipidemia and hyperuricemia, gastrointestinal symptoms, renal stones, osteopenia and cardiac problems like QT prolongation and cardiomyopathy [36,59]. An uncommon yet reported complication is protein-losing enteropathy [60], and while this can be corrected for by cessation of KD, the likely consequence is an increase in seizures. Like osteoporosis and Vitamin D alterations, which may not be relevant in the setting of acute KD administration for RSE, these complications are less relevant in the setting of short-term KD. Rather, more relevant complications to be aware of include dehydration, hyponatremia, metabolic acidosis, hypoglycemia, gastroparesis and nausea/vomiting [5,59].
Aside from poor wound healing and critical illness myopathy, our NORSE patient tolerated KD well and was discharged after 218 days in the hospital. Additional longitudinal studies are needed to examine long-term sequelae of a high fat diet in the context of adults with SE. Future research may focus on complication rates specifically associated with acute administration of KD for adult patients with RSE/SRSE in the neurological ICU setting, as well as cessation upon symptom improvement. Our patient’s neurological examination at discharge was significant for spontaneous eye opening, orientated x 2, minimally talkative with soft but clear speech. She was able to follow simple commands like closing her eyes and wiggle her toes. Strength was 3/5 proximal upper extremity with 2/5 in distal upper and proximal lower extremity. The patient was readmitted three weeks later for cardiac arrest, with subsequent reemergence of status epilepticus. Despite EEG improvement on restarting KD, the patient was eventually transitioned to comfort measures only.
19. Future of KD in Adult SE/RSE/SRSE/NORSE
While the utility of KD in adult populations is certainly promising for the management of RSE and SRSE, there remain several gaps, including a lack of standardized treatment approach, lack of randomized, double-blind controlled studies and hidden carbohydrate sources, which may impair production of ketone bodies. These inconspicuous carbohydrates are found in commonly administered medications for SE including benzodiazepines, antibiotics, electrolyte repletion formulations and even solutions used for oral care. This review offers a brief outline of treatment strategies for KD use in adults and a systematic approach for successfully achieving, maintaining and eliminating ketosis.
Acknowledgments
Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
Conceptualization, C.B.M., J.B.K., K.O.; Methodology, C.B.M., J.B.K., K.O.; Data Curation, C.B.M., M.C.C., L.J.H., K.O.; Writing—Original Draft Preparation, J.B.K..; Writing—Review & Editing, I.N., R.B., N.A.D., E.J.G., C.B.M.; Visualization, J.B.K., C.B.M., Supervision, C.B.M.; Project Administration, C.B.M.; Software, NA; Validation, NA; Formal analysis, NA; Investigation, NA; Resources, NA; Funding, NA. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
This report is a case study, therefore not meeting the Common Rule definition of research as it is not designed to develop generalizable knowledge and did not required ethical approval.
Informed Consent Statement
Given the retrospective nature of this report, the fatal outcome, and the lack of identifiable information, family was not contacted to obtain informed consent.
Conflicts of Interest
The authors declare no conflict of interest. Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
Appendix A
Briviact (brivaracetam injection) [package insert]. Smyrna, G. and I.R.M. UCB.
Cerebyx (fosphenytoin sodium injection) [package insert]. New York, N. and I.R.F. Pfizer.
Propofol injectable emulsion [package insert]. Lake Forest, I. and I.R.M. Hospira.
Ketalar (ketamine hydrochloride injection) [package Insert]. Chestnut Ridge, N., P. Pharmaceutical, and R.A. 2020.
Vimpat (lacosamide injection) [package insert]. Smyrna, G. and I.R.N. UCB.
Midazolam hydrochloride injection [package insert]. Lake Forest, I. and I.R. Hospira.
Thiopental sodium injection [package insert]. Galashiels, U. and L.R.O. Kyowa Kirin.
Valproate sodium injection [package insert]. Eatontown, N. and W.-W.P.C.R.M. 2019.
Sulfamethoxazole and trimethoprim injection [package insert]. Morgantown, W. and M.I.L.R.D. 2020.
Vancomycin hydrochloride for injection [package insert]. Rockford, I. and M.I.L.R.J. 2018.
Carbatrol (carbamazepine extended-release tablet) [package insert]. Lexington, M. and I.R.N. Takeda Pharmaceuticals America.
Levetiracetam immediate-release tablet [package insert]. Chestnut Ridge, N. and P.P.R.S. 2020.
Metamucil (psyllium husk powder) [product information]. Cincinnati, O. and P.G.R.D. 2019.
Divalproex sodium extended-release tablets [package insert]. Bridgewater, N. and A.P.L.R.A. 2020.
Peridex (chlorhexidine gluconate 0.12%) [package insert]. 3M Canada Company Dental Products. 2007.
Figure 1 Drug Interference with achievement of ketosis. Seizure Activity: On HD 14–16, seizure burden was 90% nonconvulsive status epilepticus (NCSE) and decreased to 10–15% by hospital day (HD) 23–24. From HD 30–39, % ictal ranged from 5–20% with HD 40 showing <1% ictal. % Ictal increased briefly during HD 41–47 with an average of 15% ictal but decreased to <1% by HD 48/49. % Ictal remained in the 10–20% range until HD 57 with % ictal < 1. From HD 58–72 % ictal ranged from 5–20% until % ictal <5 by HD 72.
jcm-10-00881-t001_Table 1Table 1 Summary work-up for New-Onset Refractory Status Epilepticus (NORSE) patient.
Categories Serum CSF Imaging Pathology
Infectious: Influenza A/B, H1N1, RPR, HIV, cat scratch panel, tick borne panel, Mycoplasma pneumonia, B Henselae, B quintana (all negative) West Nile Virus, Enterovirus, Bacterial culture, HSV, VZV, Lyme disease, fungal culture, HHV6, EBV, Mycoplasma pneumoniae (all negative)
Inflammatory: ANA, dsDNA, SSA, SSB, SCL 70, CRP, ESR, TPO antibody, thyroglobulin antibody, complements (C3, C4, CH50), ANCA, B2 glycoprotein, anticardiolipin, Antiribosomal P protein Ab, ACE, smooth muscle antibody, skeletal muscle antibody AMPA-R Ab, CASPR2 Ab, DPPX Ab, GABA-B-R Ab, GAD 65, GFAP, LGI1-IgG, mGluR1 Ab, NMDA R Ab
Paraneoplastic: GAD 65, NMDA, voltage gated potassium channel antibody, flow cytometry AChR ganglionic neuronal Ab, Amphiphysin Ab, Antiglial nuclear Ab, Antineuronal nuclear Ab, CRMP-5, Neuronal (V-G) K+ channel Ab, N-Type Calcium channel ab, P/Q type calcium channel Ab, Purkinje cell cytoplasmic Ab, Striational Ab (all negative)
Metabolic: TSH (0.22), Free T4 (1.7 ng/dL), Ammonia (47, 33, 37 µL/dL), serum and urine toxicology (negative)
MRI brain w/wo contrast: restricted diffusion and hyperintense FLAIR signal in the bilateral hippocampi Benign ovarian cyst
CT Chest/abdomen/pelvis: no evidence of ovarian teratoma or other malignancy No malignant cells in CSF
US pelvis: tiny 3–4 mm echogenic focus on the left ovary which may represent a small calcification, however, a tiny teratoma cannot be excluded
MRI pelvis: no evidence of ovarian teratoma
Work-up recommendations from Table 1 from Sculier C, Gaspard N. New onset refractory status epilepticus (NORSE). Seizure. 2019 May; 68:72–78. doi: 10.1016/j.seizure.2018.09.018. Epub 2018 Sep 29. PMID: 30482654. [18]. Influenza A/B: negative; H1N1: negative; Smooth and skeletal muscle antibody: negative; RPR: rapid plasma reagent—negative; ANA: antinuclear antibody—1:2560 titer; dsDNA: double-strand DNA—positive, 38.4 IU/mL; SSA: Sjögren’s Syndrome A—greater than 8; SSB: Sjögren’s Syndrome B—negative; SCL 70: Scleroderma (antitopoisomerase)—negative; Antiribosomal P protein—negative; CRP: C-reactive protein—54 mg/L; ESR: erythrocyte sedimentation rate—51 mm/h; C3/C4/CH50: within normal limits; B2 glycoprotein—negative; Anticardiolipin—negative; TPO: thyroperoxidase antibody—negative; thyroglobulin antibody—negative; ANCA: antineutrophil cytoplasmic antibody—negative; ACE: angiotensin converting enzyme—within normal limits; GAD 65: Glutamic acid decarboxylase—negative; NMDA: N-methyl-D-Aspartate receptor antibody—negative; AMPA: α-amino-3-hydroxy-5-methyl-4 -isoxazolepropionic acid receptor- antibody negative; TSH: thyroid stimulating hormone—within normal limits; HIV: Human immunodeficiency virus—negative; Lyme disease—negative; West Nile Virus—negative; Enterovirus- negative; Bacterial and fungal culture—negative; HSV: Herpes Simplex Virus—negative; VZV: Varicella Zoster Virus—negative; HHV6: Human Herpes Virus 6—negative; EBV: Epstein Barr Virus—negative; GFAP: Glial Fibrillary Acidic Protein—negative; LGI1: Leucine-rich glioma-inactivated—negative; CASPR2: Contactin-associated protein-like 2—negative; DPPX: dipeptidyl-peptidase-like protein 6—negative; GABA: gamma-aminobutyric acid—negative; mGlu1: metabotropic glutamate receptor 1—negative; CRMP-5: CV2/collapsin response mediator protein—negative; Voltage gated potassium channel—negative.
jcm-10-00881-t002_Table 2Table 2 Common antiseizure medications, medications utilized in hospitalized patients and associated carbohydrate, fat, and alcohol content.
Intravenous Product (General Product Concentration)
Carbohydrate Excipient and Amount Per Vial
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Brivaracetam (10 mg/mL) – – – –
Diazepam (5 mg/mL) [41] Propylene glycol: 414 mg 828 mg CHO/10 mg – 79 mg
Famotidine (10 mg/mL) [41] Mannitol: 20 mg 40 mg CHO/40 mg – –
Fosphenytoin [42] – – – –
Lorazepam (2 mg/mL) [42] Propylene glycol: 753 mg – – –
Pentobarbital (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Phenobarbital (130 mg/mL) [41] Propylene glycol: 702 mg – – 79 mg
Phenytoin (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Propofol (10 mg/mL) [41] Glycerol: 22.5 mg/mL 450 mg CHO/h
(20 mL/h) Soybean oil: 100 mg/mL Benzyl alcohol *
Egg Lecithin: 12 mg/mL
Lipid: 100 mg/mL
(1.1 kcal/mL)
Ketamine (multiple) – – – –
Lacosamide (multiple) – – – –
Midazolam (multiple) – – – Benzyl alcohol †
Thiopental (25 mg/mL) – – – –
Valproate (20 mg/mL) – – – –
Trimethoprim-sulfamethoxazole (Bactrim®) diluted in Dextrose 5% W 100 mL per 80–400 mg TMP-SMX Dextrose: 5 g/100 ml Up to 20 g CHO per dose – –
Vancomycin (Vancocin®) diluted in Dextrose 5% W per 1 g/250 mL solution Dextrose: 5 g/100 ml Up to 2 g CHO per dose – –
Enteral Product § (General Product Strength)
Carbohydrate Excipient and Amount Per Unit
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Carbamazepine (extended-release tablet) Lactose monohydrate ‡
Microcrystalline cellulose ‡ – – –
Clobazam (10 mg tablet) [43] 105.3 mg/tablet ≈100 mg/10 mg – –
Clonazepam (0.5 mg tablet) [43] 143.5 mg/tablet ≈2800 mg/10 mg – –
Levetiracetam (immediate release tablet) Croscarmellose sodium ‡
Polyethylene glycol 3350 ‡
Polyethylene glycol 6000 ‡ – – Polyvinyl alcohol
Psyllium (Metamucil) packet 9 g CHO/tablespoon 27 g CHO/day (TID) – –
Divalproex sodium (extended-release tablet) Hypromelloses ‡
Lactose monohydrate ‡
Polyethylene glycol ‡
Propylene glycol ‡
Macrogol ‡
Microcrystalline cellulose ‡ – – n-Butyl alcohol
Isopropyl alcohol
Polyvinyl alcohol
See Appendix A for package inserts. * Present at 1.5 mg/mL in all vial sizes (0.15% w/v). Avoid use in pediatric populations due to benzyl alcohol content. † Present at 10 mg/mL in all vial sizes (1% w/v), except preservative-free formulations. Avoid use in pediatric populations due to benzyl alcohol content. ‡ Unknown amount of relative excipient may affect ketosis but is likely clinically insignificant. § Solution and suspension formulations should be avoided if possible as they usually contain sugars that will affect ketosis.
jcm-10-00881-t003_Table 3Table 3 Ketogenic Diet checklist for Status Epilepticus.
Pearls to Consider for Starting and Maintaining a Ketogenic Diet (KD)
I. KD initiation
○ Check fasting lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D serum levels
○ Record baseline weight and height
○ Continuous video EEG
○ Dietitian/nutrition consult (consider pediatric nutritionist)
○ Stop current enteral formula
○ Reduce carbohydrate content in medications and parenteral fluids with pharmacy input
○ Active communication with nursing/pharmacy, EMR warnings, and signs in room are crucial to avoid medication/IV-containing carbohydrates
○ Begin KD (e.g., KetoCal/MCT oil)
○ Include multivitamin injection, Vit. D and calcium supplementation via nasogastric tube/gastric tube
○ Change any oral agents from liquid formulation to crushed tablet formulation
II. KD maintenance
○ Remove all common carbohydrate excipients in intravenous fluids, including:
○ Glycerin
○ Maltodextrin
○ Propylene glycol
○ Sugars (dextrose, fructose, glucose, lactose, sucrose, corn syrup)
○ Sugar alcohols (glycerol, mannitol, sorbitol)
○ Starches
○
KD can be challenged via coadministration of other meds & IVs!
III. Pitfalls to consider:
○ Contraindications: unstable metabolic derangements, hemodynamic instability, coagulopathy/bleeding diathesis, pancreatitis, liver failure, severe hyperlipidemia, ileus, pregnancy, known fatty acid oxidation disorder or pyruvate carboxylase deficiency
○
Propofol infusions cannot be given within 24 h before starting a KD!
Adapted & modified from Table 3 from Thakur KT, Probasco JC, Hocker SE, et al. Neurology. 2014 Feb 25; 82(8): 665–670. [4]. | 2 MILLIGRAM, UNK | DrugDosageText | CC BY | 33671485 | 19,466,490 | 2021-02-22 |
What was the dosage of drug 'PROPOFOL'? | Pearls and Pitfalls of Introducing Ketogenic Diet in Adult Status Epilepticus: A Practical Guide for the Intensivist.
Background: Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of a ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and effective. Methods: We describe our experience, including the challenges of achieving and maintaining ketosis, in an adult with new onset refractory status epilepticus (NORSE). Case Vignette: A previously healthy 29-year-old woman was admitted with cryptogenic NORSE following a febrile illness; course was complicated by prolonged super-refractory SE. A comprehensive work-up was notable only for mild cerebral spinal fluid (CSF) pleocytosis, elevated nonspecific serum inflammatory markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI). Repeat CSF testing was normal and serial MRIs demonstrated resolution of edema and diffusion restriction with progressive hippocampal and diffuse atrophy. She required prolonged therapeutic coma with high anesthetic infusion rates, 16 antiseizure drug (ASD) trials, empiric immunosuppression and partial bilateral oophorectomy. Enteral ketogenic formula was started on hospital day 28. However, sustained beta-hydroxybutyrate levels >2 mmol/L were only achieved 37 days later following a comprehensive adjustment of the care plan. KD was challenging to maintain in the intensive care unit (ICU) and was discontinued due to poor nutritional state and pressure ulcers. KD was restarted again in a non-ICU unit facilitating ASD tapering without re-emergence of SE. Discussion: There are inconspicuous carbohydrates in commonly administered medications for SE including antibiotics, electrolyte repletion formulations, different preparations of the same drug (i.e., parenteral, tablet, or suspension) and even solutions used for oral care-all challenging the use of KD in the hospitalized patient. Tailoring comprehensive care and awareness of possible complications of KD are important for the successful implementation and maintenance of ketosis.
1. Introduction
Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and potentially effective [1,2,3,4,5]. Most often used in childhood epilepsies, KD has emerged as a potential adjunctive treatment for pediatric SE [6,7]. We describe our experience with an adult with new onset refractory status epilepticus (NORSE) focusing on the unexpected challenge of achieving and maintaining ketosis. Practical advice, and a comprehensive review of factors potentially jeopardizing ketosis commonly encountered in the critical care setting and alternatives are provided.
2. Presentation
A previously healthy 29-year-old woman was admitted to another institution with new onset refractory status epilepticus (NORSE) following a febrile illness with a course complicated by prolonged super-refractory SE. Three days prior to presentation she developed fever, headache, emesis and fatigue in the setting of being in contact with her child with an upper respiratory tract infection. On the morning of admission, her friend attempted to awaken her for work and found her unresponsive and convulsing. In the emergency department, she was lethargic and mumbling incoherently. During her initial evaluation she had a witnessed 45-s bilateral tonic-clonic seizure that was aborted with 2 mg lorazepam intravenously. Head computed tomography was unremarkable and initial cerebrospinal fluid (CSF) analysis showed a mononuclear pleocytosis (2 RBC, 41 nucleated cells (57% mononuclear cells), glucose 93, protein 54)). A one-hour electroencephalogram (EEG) showed diffuse delta activity admixed with sleep spindles and K complexes without epileptiform discharges. She was monitored in the step-down unit and treated with levetiracetam and acyclovir. On hospital day two, she was somnolent but arousable to voice; she was able to follow simple midline commands, state her name and the current president, but was disoriented to time. She was noted to have twitching of her face, but no EEG was done at that time. By hospital day three, she began experiencing brief convulsive seizures which were aborted with intravenous lorazepam and always associated with recovery of consciousness. At that point, phenytoin (1 g loading dose, maintenance at 100 mg q8h) was added to her antiseizure drug (ASD) regimen. On hospital day four, she had multiple convulsive seizures without return to baseline, complicated by acute hypoxic respiratory failure requiring intubation. She was transferred to the intensive care unit (ICU) where she was started on propofol, and valproic acid (20 mg/kg loading dose, maintenance at 750 mg Q8H) was added. Routine EEG captured multiple discrete right frontal and centrotemporal onset seizures correlating with episodes of face twitching. She was started on pentobarbital infusion (5 mg/kg bolus, maintenance at 1 mg/kg per hour) and transferred to our center for continuous EEG monitoring.
3. Question: How Is Prolonged Seizure Activity Classified and What Are Potential Etiologies to Be Considered?
According to the most recent classification set by The International League Against Epilepsy, SE is a “condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures” [8]. While operational SE definitions based on time-domains vary according to seizure type, it is generally accepted that convulsive seizure activity lasting either greater than 5 min continuously, or two or more seizures during which the individual does not recover to baseline between seizures, represents SE [8]. Inhibitory gamma-aminobutyric acid (GABA) neurons located in the pars reticulata of the substantia nigra are key in seizure termination [9]. During status epilepticus, marked alteration of GABA metabolism occurs in this region and results in disinhibition of excitatory pathways: GABA synthesis slows down [10]. GABA turnover time increases up to three-fold, [10] and GABA receptors (originally located in the surface of the cell membrane) migrate to the intracellular space within minutes of ongoing seizure activity [11,12,13]. Prompt initiation of abortive therapies is key, as the internalization of GABA receptors contributes to refractoriness to treatment.
Emergent administration of parenteral benzodiazepine (e.g., up to 0.1 mg/kg of lorazepam) is considered the first-line therapy for SE [14]. If a patient fails to respond to a benzodiazepine and a second appropriately selected and dosed ASD at adequate doses, they are in refractory status epilepticus (RSE). It has been reported that one in five RSE patients go on to develop super-refractory status epilepticus (SRSE), defined as (1) ongoing seizures lasting 24 h or more after onset of anesthetic therapy (i.e., propofol) or (2) recurrence of SE upon reduction or withdrawal of therapeutic anesthetic coma [15]. The clinical presentation of RSE in patients without overt acute or remote brain injury, prior epilepsy, or acute toxic/metabolic explanation is consistent with New Onset Refractory Status Epilepticus—NORSE [16]. Febrile Infection-Related Epilepsy Syndrome (FIRES) is a subset of NORSE, in which a febrile infectious illness precedes SE onset by 1–14 days [14,15,16]. Thus, our patient qualified as having the syndrome of FIRES as well as NORSE. Further, clinical criteria for unequivocal electroencephalographic status epilepticus in patients without known epileptic encephalopathy has been established in the Salzburg consensus: (1) repeating epileptiform discharges occurring >2.5 Hz, or (2) repeating epileptiform discharges occurring ≤2.5 Hz or rhythmic delta/theta activity >0.5 Hz plus (a) electroclinical response (improvement) following intravenous ASD challenge, (b) subtle clinical correlate associated with pattern, or (c) typical temporal and spatial evolution of pattern [17].
Determining the underlying etiology of SE may seem a daunting task. However, its importance in achieving seizure cessation cannot be underestimated. Outcome following SE is dependent on the etiology of seizures. Further, appropriately recognizing the electroclinical classification of seizures (i.e., identifying the seizure semiology and its electrographic signature) may not only help selection of therapy but also identify potential etiologies [8]. Among NORSE patients, an etiology is found in up to 50% of cases [16]. Of those with an identifiable cause, the majority (37%) had an autoimmune cause (both nonparaneoplatic and paraneoplastic), while 8% had a probable infectious cause [16]. Thus, if an autoimmune etiology is diagnosed or clinically suspected, immune modulating therapies such as high-dose corticosteroids, intravenous immunoglobulin (IVIg) or plasma exchange therapy, followed by monoclonal antibodies and/or interleukin inhibitors, should be considered early in the course.
Our patient underwent a comprehensive work-up to determine the etiology of NORSE, as summarized on Table 1, which was notable only for mild CSF pleocytosis, elevated nonspecific inflammatory serum markers and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI).
4. Question: What Are the Initial Steps in the Therapeutic Algorithm for Status Epilepticus?
Benzodiazepines are the first-line treatment for SE [14,19] with slower-acting, less sedating parenteral ASDs being the second line (e.g., phenytoin, fosphenytoin, valproate and levetiracetam; and possibly lacosamide and phenobarbital). The Established Status Epilepticus Treatment Trial (ESETT) found no difference in efficacy between fosphenytoin (20 mgPE/kg), valproate (40 mg/kg) and levetiracetam (60 mg/kg) in children, adults and older adults; these ASDs were able to abort SE within an hour in nearly 50% of patients [20]. Once the second-line, or a combination of medications, fails to result in seizure cessation, continuous intravenous infusions of anesthetics (i.e., midazolam, pentobarbital, propofol, ketamine) are often recommended [14,19].
In patients with SE, anesthetic use is associated with longer hospital stay, but not in-hospital or 90-day mortality [21]. Amongst NORSE patients who receive anesthetics, the mortality is high. However, the use of anesthetics is not associated with poor outcome [16]. In 61 patients with RSE, those who underwent deep sedation (defined as either EEG showing burst suppression or isoelectric activity) had both poorer long-term prognosis and increased mortality [22]. Burst suppression on EEG is defined as intermittent alternating periods of low amplitudes (<10 uV for burst suppression; 10–20 uV for burst attenuation) interrupting a background, which may consist of waves of varying frequencies. Earlier attainment of burst suppression may allow for a more rapid anesthetic wean [23], and it is important to frequently monitor the EEG and titrate anesthetic dose as appropriate. The goal of anesthetic use in RSE is the resolution of epileptiform activity in order to avoid physiologic effects while the underlying cause is identified and treated [24,25].
In our case, 16 antiseizure drug trials in various combinations and high anesthetic infusion rates were attempted. RSE persisted despite 160 mg/h (2.5 mg/kg/h) of midazolam prompting the initiation of ketamine. Despite improved seizure burden following ketamine bolus (1.5 mg/kg), reemergence of SE occurred despite up-titration of ketamine to our maximum infusion rate (7.5 mg/kg/h). Her EEG responded to propofol and pentobarbital with long periods of suppression, although her background remained with abundant generalized periodic discharges (GPD) at 2.5–3 Hz, qualifying as ongoing electrographic SE. [17,26] Burst suppression was eventually achieved with pentobarbital at 3 mg/kg/h and propofol at 40 mcg/kg/min. However, due to re-emergence of 2 Hz GPDs along with breakthrough seizures on attempted wean, she remained in a medically induced coma for over three months.
5. Question: What Are Potential Rescue Therapeutic Approaches to the Management of Super-Refractory Status Epilepticus?
Refractory and super-refractory SE and their complications are associated with significant morbidity including death, neuronal damage and systemic complications like cardiomyopathy, ischemic bowel, pulmonary edema and renal failure [27]. This highlights the necessity for a prompt and aggressive treatment approach. In the setting of treatment failure, alternative treatment options include inhaled anesthetics, magnesium infusion, pyridoxine, hypothermia, electrical and magnetic stimulation, additional immunotherapy, enteral ASDs and the KD [28].
Given a high suspicion for an autoimmune process, our patient was treated with intravenous methylprednisolone (1 g daily for 5 days), IVIg, plasma exchange and cyclophosphamide. Serial MRIs demonstrated resolution of edema and diffusion restriction with gradually progressive atrophy, predominantly in the hippocampi, and repeat CSF analysis was normal. She underwent empiric bilateral partial oophorectomy for an echogenic focus in her left ovary and concern for possible occult microteratoma, possibly secondary to N-methyl-D-Aspartate (NMDA) encephalitis (NMDA CSF < 1:1 and serum < 1:10) [29].
6. Ketogenic Diet
Ketosis is commonly defined as sustained beta-hydroxybutyrate levels > 2 mmol/L [30] or a urinary acetoacetate level of >40 mg/dL [31]. There is evidence supporting the use of KD in children with autoimmune epilepsies, symptomatic epilepsy syndromes, pediatric refractory and super-refractory SE [6,32]. In a study of 10 children (age six months—16 years old) with refractory focal SE, initiation of a KD resulted in lower seizure burden (50% reduction in seizures for 70% of the cohort) and resolution of seizures in 20% [6]. In the minority of patients with less than 50% seizure reduction (n = 3), severe adverse events (pancreatitis or severe vomiting and hypoglycemia) prompted KD discontinuation. In another study of 12 children with fever induced refractory epileptic encephalopathy, KD was able to stop seizures within two days following ketonuria [32]. Nevertheless, the side effects of KD limit its widespread use, and successful ketosis must be attained for seizure control.
More recently, KD has been evaluated in adult patients; a systematic review of 38 adult patients with RSE or SRSE demonstrated that 82% were able to achieve SE cessation with KD [33]. There are several complex mechanisms for the efficacious effect of KD on reducing seizure activity, which result from reduction in glucose intake, ketone body production and alteration of the gut microbiome. The metabolic changes induced by KD alter the balance of excitatory and inhibitory neurotransmitters, lead to reductions in oxidative stress and systemic as well as neuroinflammation, and have further long-term effects on gene expression [3,34].
We sought KD as a rescue therapy after conventional treatments had failed.
7. Question: What Are Some Factors Should the Clinician Consider When Selecting and Initiating KD for Adults with SE?
Initiating KD Safely
Determining the optimal patient for whom to implement KD requires a comprehensive evaluation of the patient’s past medical history, comorbidities and current clinical status. As with all treatment strategies, particularly in the ICU setting, a thoughtful risk-benefit analysis is warranted. Inborn errors of metabolism are a contraindication to KD [35,36]. However, these conditions most often present in early childhood, and rarely in adults, so screening is not routinely obtained prior to KD initiation in adults [1,2]. Other contraindications of KD include unstable metabolic (mitochondrial enzyme deficiencies) conditions, liver failure, acute pancreatitis, pregnancy and an inability to tolerate enteral feeds [5]. Protocols typically avoid starting KD within 24 h of propofol infusions to avoid possibly fatal propofol infusion syndrome, characterized by metabolic acidosis, lipemia, rhabdomyolysis and myocardial failure [37].
8. Question: Should You Fast the Patient to Achieve Ketosis Quickly? If So, How Long and What Are Potential Consequences? If You Decide Not to Fast, Can Ketosis Still Be Achieved?
Variations in KD Protocols
Historically, KD implementation in the setting of childhood epilepsy included an initial fasting period ranging anywhere from 12 [7] to 48 [36,38] hours or more. Once satisfactory ketosis is achieved, ketogenic formulations or meals (typically 4:1 g of fat: carbohydrate + protein ratio) can then be titrated as tolerated until full caloric requirements are met. To avoid potential complications of a fasting period (e.g., dehydration, hypoglycemia), Kim et al. began KD without initial fasting and found equivalency in time to ketosis and seizure reduction in 41 children with intractable epilepsy compared to a retrospective control population of 83 children who fasted prior to KD initiation [39]. While rates of hypoglycemia were similar when compared to controls, there were reduced rates of dehydration and reduced length of hospital stay.
An alternative, yet equally efficacious approach for childhood epilepsy, does not involve initial fasting or limiting caloric intake. This protocol differs from others in the fact that there is a gradual increase from 1:1 to 2:1 until the goal 4:1 ratio is reached [38]. This gradual induction and establishment of ketosis in children diagnosed with intractable epilepsy showed an equal reduction in seizure activity yet decreased weight loss and episodes of hypoglycemia, acidosis and dehydration. Nevertheless, since time is a major factor in terms of avoiding neurologic and systemic consequences of SE, a more aggressive approach to KD initiation (i.e., fasting and/or more rapidly advancing to full calories as tolerated) may be warranted in this setting.
Individual patient characteristics including age, illness severity, duration of anesthetic use prior to diet initiation resulting in reduction in gastrointestinal motility, and diet complications, may not allow the luxury of initiating a preferred protocol with certain ketogenic ratio or at a faster rate. This was evident in Cobo’s pediatric SRSE study in which ratios were started as low as 0.75:1 in some instances, and ratios never exceeding 2:1 in some cases [7]. The need for higher protein intake (often in cases of poor wound healing, malnutrition and/or low basal resting energy expenditure) challenges the use of higher fat:protein + carbohydrate ratios, although this is more of a concern with chronic KD use rather than in the acute setting of RSE and SRSE. A possible way to maximize ketosis when using lower ratios (thus, higher protein intake) is the addition of medium-chain triglyceride oils as they yield greater amounts of ketones/kcal of energy than longer chain varieties [36].
We used these principles, most frequently used in the setting of childhood epilepsy, to initiate KD for our NORSE patient with the goal of achieving ketosis quickly. Our patient was initially started on KD on hospital day 28 (HD 28) with a goal of 5:1 ratio (KetoCal® 4:1 at 55 mL/h plus 33 mL medium-chain triglycerides (MCT) oil to balance carbohydrate intake from medications, documented as 51 g daily on HD 30). At this time, supplemental protein via PROsource® was discontinued to assist with achieving ketosis. On HD 35, beta-hydroxybutyrate (BHB) levels continued to show inadequate ketosis [Figure 1] prompting the increase to 6:1 with additional MCT Oil. Through HD 65, beta-hydroxybutyrate continued to fluctuate below the 2.0 goal. On HD 71, beta-hydroxybutyrate again dropped with the only documented potential carbohydrate source (at that time) being a milk and molasses enema administered by a care team to alleviate constipation. The decision was made to return to a higher carbohydrate-containing formula and refocus nutrition goals on wound healing. At this time, our patient was identified as meeting the criteria for severe malnutrition based on weight loss of >7.5% in three months and limited energy intake for greater than or equal to five days [40].
9. Question: What Factors Can Impede the Success of Achieving Ketosis, and thus Jeopardize the Utility of KD?
Despite initiating KD with complete enteral feeds on hospital day 28, our patient was only able to reach ketosis a significant 37 days later (Figure 1). After a comprehensive assessment of the care plan, the culprit was found: inconspicuous carbohydrate-containing medications, infusions and oral-care solutions routinely given in the setting of a neurological ICU (Table 2).
10. Hidden Carbohydrates Can Hinder Achievement of Ketosis
In our experience, the most likely medication-induced barriers to ketosis include sedatives, antiseizure drugs and antibiotics. Benzodiazepines are not created equally when it comes to hidden/nonobvious carbohydrate content. Diazepam (Valium® 5 mg/mL) and Lorazepam (Ativan® 2 mg/mL) have been shown to have 40% and 80% propylene glycol content, respectively, which equates to an overall carbohydrate content of 0.4 g/mL and 0.8 g/mL [42]. Intake of this carbohydrate content in patients with status epilepticus on KD may hinder achieving ketosis, but can also precipitate propylene glycol toxicity and associated anion-gap, metabolic acidosis [44].
While the carbohydrate load of each individual dose may be inconsequential, the cumulative dose given to patients in extended hospital stays may be significant. For example, initial administrations of injectable lorazepam, 2 mg every 6 h yields approximately 3 g of carbohydrate per day [44]. For context, this patient’s energy assessment used an ideal body weight of 64.5 kg, with daily caloric requirements calculated to total 2260 kcal/day (35 kcal/kg). Using KD at a 4:1 ratio (a common target for KD), the macronutrient breakdown is 226 g fat, 51.6 g protein, and 4.9 g carbohydrates. Thus, lorazepam would have contributed over half of the allotted daily carbohydrate load. Figure 1 shows several instances where lorazepam administration was associated with significant troughs in beta-hydroxybutyrate levels. When benzodiazepine infusions are warranted for refractory cases, our recommendation would be to consider midazolam as an alternative; midazolam does not have propylene glycol in its formulation, resulting in lower rates of anion-gap metabolic acidosis [45]. Regarding enteral administration of benzodiazepines, it is worth noting that clobazam (Onfi ®) and clonazepam (Klonopin®) contain 105 mg and 143.5 mg of carbohydrates (i.e., lactose, starch) per 10 mg/0.5 mg tablet, respectively [Table 2]. When selecting benzodiazepines for treatment of SE in patients treated with KD, it is important to evaluate the carbohydrate content for the selected benzodiazepine and the administration method. Generally, solutions and suspensions should be avoided due to high carbohydrate containing excipients.
Another class of widely used sedatives, often with the potential to inadvertently hinder beta-hydroxybutyrate levels, are the barbiturates, particularly pentobarbital (Nembutal® 50 mg/mL) and phenobarbital (Phenobarb® 130 mg/mL). Barbiturates are commonly used in RSE. However, they have a high propylene glycol content (pentobarbital 414 mg/50 mg vial, phenobarbital 702 mg/130 mg vial [42] amounting to an overall carbohydrate content of 2.9 g/h when pentobarbital is infused at a rate of 5 mg/kg/h for a 70 kg patient) [Table 2]. We suggest that ketamine (and midazolam, as discussed above) be considered as an alternative to pentobarbital in patients with status epilepticus on KD, given their lack of propylene glycol [46], This same concept can be applied for phenytoin (Dilantin® 50 mg/mL), which contains 40% propylene glycol [42] amounting to a carbohydrate content of 414 mg (plus an additional 79 mg of alcohol). These principles can be observed in Figure 1 where beta-hydroxybutyrate levels drop on HD 52, corresponding with a phenobarbital load (a disruption in feeds also occurred to administer phenytoin by mouth). We recommend that fosphenytoin be used instead to avoid propylene glycol excipients (Table 2). Similarly, on HD 56, beta-hydroxybutyrate dropped to 0.63 mmol/L with a medication review showing intravenous phenobarbital administered overnight. Lastly, another note of caution regarding anesthetic infusions: propofol contains 1.1 kcal/mL (mostly from fats), which provides approximately 528 kcal per day (presuming 20 mL/h). While this increased caloric load may aid in ketosis, its 450 mg of glycerol per 20 mL vial may hinder ketosis (Table 2).
11. Noncarbohydrate Related Hindrance of Ketosis
Among children with refractory epilepsy, concomitant lamotrigine use decreases KD’s efficacy in seizure reduction [47]. This may be explained by ketosis increasing the metabolism/inactivation of lamotrigine via glucosyltransferases, which ultimately results in increased glutamate release. Lastly, one must not forget that while medication use can influence KD, the inverse is also true. While most serum concentrations of ASD were not found to significantly change upon KD use, valproic acid levels have been shown to decrease [48]. Therefore, it is recommended to monitor valproic acid while using KD therapy.
12. Question: Aside from Sedative Agents, What Other Widely Used Agents in the Neurological ICU Can Hinder Ketosis?
12.1. Antimicrobials and Respective Diluents as Source of Carbohydrates
Various antibiotics that are used frequently in the neurological ICU [49,50] can hinder ketosis. Intravenous trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim®) requires reconstitution with dextrose 5% water and, similarly, vancomycin is often diluted in dextrose 5% water prior to intravenous administration (Table 2). Figure 1 (line graph) shows several instances in which administration of TMP-SMX and vancomycin were associated with troughs in beta-hydroxybutyrate levels.
12.2. Non “Medications” Contain Hidden Carbohydrates
Hidden carbohydrates are found in oral care solutions such as chlorhexidine, dietary supplements and fiber. Chlorhexidine 0.12% oral solution (PeridexTM), reported to be superior to toothbrushing at reducing early ventilator-associated pneumonia [51], contains glycerin and ethyl alcohol (see Appendix A), both carbohydrate-containing substances that can affect KD [52]. Oral fiber supplements, such as psyllium, have a significant carbohydrate load (e.g., 9 g/tablespoon) (Table 2). However, as fiber has a lower glycemic index compared to other carbohydrate-containing sources in the ICU setting, it may still be used in some instances to counteract constipation.
12.3. Comprehensive Approach to Implementing KD in Adult SE
Adopting a systematic approach is key for the successful implementation and maintenance of a ketotic state. A checklist is provided in Table 3 with a summary of the suggested steps for successful KD initiation [4].
13. Question: What Laboratory Values Should the Intensivist Pay Particular Attention to When Using KD?
Baseline assessment of certain serum (lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D, and free and total carnitine) [41] and anthropometric (weight, height) parameters [5,33,53] are imperative to effectively see how values trend overtime with KD. This objective data collected longitudinally allows monitoring of metabolic and systemic side effects of KD to allow for cessation if need-be.
After deciding that KD is appropriate, the next step is to carefully review all standing orders in the patient’s chart to identify potential sources of hidden carbohydrates and replace with alternatives. Guidance by the dietary/nutrition team as well as an ICU pharmacist are recommended to improve success with achieving and maintaining ketosis. If possible, a nutritionist with knowledge and experience with managing a KD is preferred, which may necessitate involving the pediatric nutrition team.
In the critical care setting, nutrition is often dictated by the critical care team via administration of formula tube feeding, and patient compliance is not a key factor for achieving ketosis. Route of administration does impact ketosis as suspension or elixir medications, [53] the preferred formulations via percutaneous gastrostomies (PEG) or other enteral routes, must be replaced by alternative formulations with lower carbohydrate content [7]. Additionally, dextrose-free diluents [52] must be used whenever able in intravenous drug formulations. Unavoidable carbohydrates can be balanced with a calculated dose of fat in the form of MCT oil or a commercially available emulsified oil (provided that this addition coincides with caloric and macronutrient percentages discussed later). Additionally, this puts the patient at an increased risk for gastrointestinal complications such as steatorrhea, emesis and reflux.
14. Ketosis Maintenance and Surveillance
Inducing ketosis is only the first step in tackling SE. While a ketotic state is commonly defined as beta-hydroxybutyrate >2 mmol/L [30], similarly to antiseizure drugs, some individuals require higher level of ketosis (or antiseizure drugs) to achieve optimal seizure control. Thus, individual thresholds for optimal ketotic state may vary. In the presented case, the best therapeutic effect was noted with beta-hydroxybutyrate >3.5. Maintaining ketosis above a certain therapeutic level proves to be difficult, particularly when higher targets are required such as >3 mmol/L beta-hydroxybutyrate [7]. For example, Cobo’s case series illustrated that children with SRSE can have sudden, unexplained drops in beta-hydroxybutyrate levels.
After KD was stopped on HD 73 due to poor nutritional status, KD was reinitiated on HD 106 as the patient was no longer on bolus medications with high carbohydrate content. Ketosis was achieved rapidly over two days, with a beta-hydroxybutyrate of 2.34 mmol/L target once the goal of 6:1 ratio 18 kcal/kg was reached. The rapid achievement of ketotic state likely resulted from several days of fasting prior to its initiation in the setting of percutaneous gastrostomy placement and enterocutaneous fistula repair. The patient remained in ketosis, with beta-hydroxybutyrate levels fluctuating between 1.93–5.32 mmol/L, during which time seizures were best controlled when beta-hydroxybutyrate levels were >3.5 mmol/L.
Constant evaluation and re-evaluation of patient intake, including intravenous fluids, must be conducted. It is imperative to remove all common exogenous carbohydrates including glycerin, maltodextrin, propylene glycol, dextrose, fructose, glucose, lactose, sucrose, corn syrup, sugar alcohols and starches [52]. Appropriate alternatives include normal saline, balanced crystalloid or lactated Ringer’s solution.
15. Question: What Natural Physiologic Mechanisms Must Be Accounted for When Attempting to Achieve/Maintain Ketosis?
In addition to exogenous carbohydrate management, the intensivist must not overlook endogenous perturbations of glucose homeostasis. Commonly measured anywhere from every four [54] to eight hours after initiation of KD [7], fluctuations are commonly seen in the pediatric population as the clinician attempts to titrate to a glucose target level of 60–79 mg/dL [7]. While the lower limit of 40 mg/dL is referenced in the Academy of Nutrition and Dietetics Practice Paper, the clinicians at Yale New Haven Hospital use a slightly higher limit of 50 mg/dL when evaluating for KD initiation. Ketosis can be threatened by endogenous gluconeogenesis occurring during infection or injury [55]. The topic of glucose perturbations brings up the discussion of whether the use of glucocorticoids concurrently with KD hinders the diet’s efficacy. Among children with epilepsy being treated with KD, there have been reports of glucocorticoid use (even inhaled) being associated with seizure return, elevated glucose and ketosis hindrance [56]. More studies are needed to examine the relationships of KD and glucocorticoid use in the setting of SE/RSE.
16. KD and Supplements
Question: What Supplements may Be Warranted when Starting a Ketogenic Diet?
The KD’s inherent shift into fatty acid beta-oxidation predisposes to metabolic acidosis, which can be further compounded if individuals are fasting to achieve ketosis [36]. For these reasons, adequate bicarbonate levels (commonly >17 mmol/L) [7] should be ensured with concomitant sodium bicarbonate [5] and/or potassium citrate supplementation [7].
Beta-oxidation in the mitochondria is reliant on the adequate transport of long-chain fatty acids across the mitochondrial membrane via carnitine [36,53]. Carnitine supplementation is recommended when levels are low (<30 μmol/L) or if the patient is symptomatic, defined by lethargy, weakness and GI symptoms, which are often difficult to assess in a comatose patient [7,36,53]. Carnitine supplementation remains controversial, as levels poorly correlate with tissue stores and symptoms of carnitine deficiency may be difficult to identify in comatose patients [53].
Lastly, it is recommended that a low carbohydrate multivitamin, calcium carbonate and Vitamin D be added [34,36] via nasogastric/gastric tube (NG/G-tube). Most commercially available ketogenic formulas have the recommended daily allowance of these substances. Children with epilepsy have hypovitaminosis D (50%) and are at risk for osteoporosis [36,53]. Phosphorous, [53] administered separately to avoid calcium chelation, is a recommended supplement for its role in bone homeostasis. Lastly, it is our recommendation to supplement either lite salt or table salt for patients that have hyponatremia despite administration of sodium containing intravenous fluids.
17. Termination of Ketotic Therapy
Question: Once Anesthetics Have Been Weaned and/or Seizure Activity Has Improved, How Should KD Be Weaned?
Reasons for diet discontinuation include lack of response, development of complications and need for optimization of nutritional status. There are no clear guidelines to define a clear response to KD, as diseases and patient populations are very heterogeneous, and a clear absolute seizure cessation effect may not be seen. In some cases, allowing for anesthetic wean or antiseizure regimen simplification may be considered successful results. It is our recommendation that before considering therapeutic failure, higher ketotic levels should be pursued if the patient is able to tolerate a more aggressive titration of the KD, as patients, such as our patient, may respond to higher beta-hydroxybutyrate levels.
Like any antiseizure therapy, it is generally recommended to wean the KD diet gradually due to the historical thought that abrupt withdrawal of ketosis can precipitate recurrence of seizures or SE. Abrupt withdrawal of KD is recommended for emergencies only. Thus, gradually reducing the ratio of grams of fats:protein + carbohydrates is recommended (i.e., 4:1 to 3:1 to 2:1) [36]. Despite there being a common notion that overzealous weaning of KD can precipitate previously suppressed seizure activity, a study of over 183 children showed no significant difference in the incidence of seizures worsening between discontinuation/weaning rates (i.e., <1 week vs. 1–6 weeks vs. >6 weeks) [57]. However, there was an increase in seizure activity with faster weaning schedules among a particular cohort: children who had higher percentage (55–90%) of seizure reduction while on the KD. Additionally, among children who successfully stopped KD after seizure cessation, 42% of them were unable to achieve symptom improvement with either ASD or reinitiating of KD upon seizure relapse [58].
We recommend that the clinician use the KD’s treatment success as well as clinical judgement in adopting an individualized weaning schedule. Beginning on HD 194, our patient was weaned from the KD over five days by decreasing the ketogenic formula by 20% every 24 h and replacing it with a traditional critical care formula. Supplemental MCT oil was decreased at the beginning of the weaning process. No complications arose during this transition. Once able to tolerate oral nutrition, the patient will have the autonomy to determine whether to continue KD and contingency plans, such as offering a less strict KD therapy (modified Atkins diet, modified KD), which may be a reasonable alternative.
18. Anticipating and Managing Complications
Question: What Are Some Potential Complications of KD?
Complications of KD are not uncommon and may result in discontinuation of the diet. In the pediatric literature, 30 [6] to 38% discontinuation rates [59] are described due to inability to tolerate the diet or due to complications. These complications include metabolic derangements like dyslipidemia and hyperuricemia, gastrointestinal symptoms, renal stones, osteopenia and cardiac problems like QT prolongation and cardiomyopathy [36,59]. An uncommon yet reported complication is protein-losing enteropathy [60], and while this can be corrected for by cessation of KD, the likely consequence is an increase in seizures. Like osteoporosis and Vitamin D alterations, which may not be relevant in the setting of acute KD administration for RSE, these complications are less relevant in the setting of short-term KD. Rather, more relevant complications to be aware of include dehydration, hyponatremia, metabolic acidosis, hypoglycemia, gastroparesis and nausea/vomiting [5,59].
Aside from poor wound healing and critical illness myopathy, our NORSE patient tolerated KD well and was discharged after 218 days in the hospital. Additional longitudinal studies are needed to examine long-term sequelae of a high fat diet in the context of adults with SE. Future research may focus on complication rates specifically associated with acute administration of KD for adult patients with RSE/SRSE in the neurological ICU setting, as well as cessation upon symptom improvement. Our patient’s neurological examination at discharge was significant for spontaneous eye opening, orientated x 2, minimally talkative with soft but clear speech. She was able to follow simple commands like closing her eyes and wiggle her toes. Strength was 3/5 proximal upper extremity with 2/5 in distal upper and proximal lower extremity. The patient was readmitted three weeks later for cardiac arrest, with subsequent reemergence of status epilepticus. Despite EEG improvement on restarting KD, the patient was eventually transitioned to comfort measures only.
19. Future of KD in Adult SE/RSE/SRSE/NORSE
While the utility of KD in adult populations is certainly promising for the management of RSE and SRSE, there remain several gaps, including a lack of standardized treatment approach, lack of randomized, double-blind controlled studies and hidden carbohydrate sources, which may impair production of ketone bodies. These inconspicuous carbohydrates are found in commonly administered medications for SE including benzodiazepines, antibiotics, electrolyte repletion formulations and even solutions used for oral care. This review offers a brief outline of treatment strategies for KD use in adults and a systematic approach for successfully achieving, maintaining and eliminating ketosis.
Acknowledgments
Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
Conceptualization, C.B.M., J.B.K., K.O.; Methodology, C.B.M., J.B.K., K.O.; Data Curation, C.B.M., M.C.C., L.J.H., K.O.; Writing—Original Draft Preparation, J.B.K..; Writing—Review & Editing, I.N., R.B., N.A.D., E.J.G., C.B.M.; Visualization, J.B.K., C.B.M., Supervision, C.B.M.; Project Administration, C.B.M.; Software, NA; Validation, NA; Formal analysis, NA; Investigation, NA; Resources, NA; Funding, NA. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
This report is a case study, therefore not meeting the Common Rule definition of research as it is not designed to develop generalizable knowledge and did not required ethical approval.
Informed Consent Statement
Given the retrospective nature of this report, the fatal outcome, and the lack of identifiable information, family was not contacted to obtain informed consent.
Conflicts of Interest
The authors declare no conflict of interest. Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.
Appendix A
Briviact (brivaracetam injection) [package insert]. Smyrna, G. and I.R.M. UCB.
Cerebyx (fosphenytoin sodium injection) [package insert]. New York, N. and I.R.F. Pfizer.
Propofol injectable emulsion [package insert]. Lake Forest, I. and I.R.M. Hospira.
Ketalar (ketamine hydrochloride injection) [package Insert]. Chestnut Ridge, N., P. Pharmaceutical, and R.A. 2020.
Vimpat (lacosamide injection) [package insert]. Smyrna, G. and I.R.N. UCB.
Midazolam hydrochloride injection [package insert]. Lake Forest, I. and I.R. Hospira.
Thiopental sodium injection [package insert]. Galashiels, U. and L.R.O. Kyowa Kirin.
Valproate sodium injection [package insert]. Eatontown, N. and W.-W.P.C.R.M. 2019.
Sulfamethoxazole and trimethoprim injection [package insert]. Morgantown, W. and M.I.L.R.D. 2020.
Vancomycin hydrochloride for injection [package insert]. Rockford, I. and M.I.L.R.J. 2018.
Carbatrol (carbamazepine extended-release tablet) [package insert]. Lexington, M. and I.R.N. Takeda Pharmaceuticals America.
Levetiracetam immediate-release tablet [package insert]. Chestnut Ridge, N. and P.P.R.S. 2020.
Metamucil (psyllium husk powder) [product information]. Cincinnati, O. and P.G.R.D. 2019.
Divalproex sodium extended-release tablets [package insert]. Bridgewater, N. and A.P.L.R.A. 2020.
Peridex (chlorhexidine gluconate 0.12%) [package insert]. 3M Canada Company Dental Products. 2007.
Figure 1 Drug Interference with achievement of ketosis. Seizure Activity: On HD 14–16, seizure burden was 90% nonconvulsive status epilepticus (NCSE) and decreased to 10–15% by hospital day (HD) 23–24. From HD 30–39, % ictal ranged from 5–20% with HD 40 showing <1% ictal. % Ictal increased briefly during HD 41–47 with an average of 15% ictal but decreased to <1% by HD 48/49. % Ictal remained in the 10–20% range until HD 57 with % ictal < 1. From HD 58–72 % ictal ranged from 5–20% until % ictal <5 by HD 72.
jcm-10-00881-t001_Table 1Table 1 Summary work-up for New-Onset Refractory Status Epilepticus (NORSE) patient.
Categories Serum CSF Imaging Pathology
Infectious: Influenza A/B, H1N1, RPR, HIV, cat scratch panel, tick borne panel, Mycoplasma pneumonia, B Henselae, B quintana (all negative) West Nile Virus, Enterovirus, Bacterial culture, HSV, VZV, Lyme disease, fungal culture, HHV6, EBV, Mycoplasma pneumoniae (all negative)
Inflammatory: ANA, dsDNA, SSA, SSB, SCL 70, CRP, ESR, TPO antibody, thyroglobulin antibody, complements (C3, C4, CH50), ANCA, B2 glycoprotein, anticardiolipin, Antiribosomal P protein Ab, ACE, smooth muscle antibody, skeletal muscle antibody AMPA-R Ab, CASPR2 Ab, DPPX Ab, GABA-B-R Ab, GAD 65, GFAP, LGI1-IgG, mGluR1 Ab, NMDA R Ab
Paraneoplastic: GAD 65, NMDA, voltage gated potassium channel antibody, flow cytometry AChR ganglionic neuronal Ab, Amphiphysin Ab, Antiglial nuclear Ab, Antineuronal nuclear Ab, CRMP-5, Neuronal (V-G) K+ channel Ab, N-Type Calcium channel ab, P/Q type calcium channel Ab, Purkinje cell cytoplasmic Ab, Striational Ab (all negative)
Metabolic: TSH (0.22), Free T4 (1.7 ng/dL), Ammonia (47, 33, 37 µL/dL), serum and urine toxicology (negative)
MRI brain w/wo contrast: restricted diffusion and hyperintense FLAIR signal in the bilateral hippocampi Benign ovarian cyst
CT Chest/abdomen/pelvis: no evidence of ovarian teratoma or other malignancy No malignant cells in CSF
US pelvis: tiny 3–4 mm echogenic focus on the left ovary which may represent a small calcification, however, a tiny teratoma cannot be excluded
MRI pelvis: no evidence of ovarian teratoma
Work-up recommendations from Table 1 from Sculier C, Gaspard N. New onset refractory status epilepticus (NORSE). Seizure. 2019 May; 68:72–78. doi: 10.1016/j.seizure.2018.09.018. Epub 2018 Sep 29. PMID: 30482654. [18]. Influenza A/B: negative; H1N1: negative; Smooth and skeletal muscle antibody: negative; RPR: rapid plasma reagent—negative; ANA: antinuclear antibody—1:2560 titer; dsDNA: double-strand DNA—positive, 38.4 IU/mL; SSA: Sjögren’s Syndrome A—greater than 8; SSB: Sjögren’s Syndrome B—negative; SCL 70: Scleroderma (antitopoisomerase)—negative; Antiribosomal P protein—negative; CRP: C-reactive protein—54 mg/L; ESR: erythrocyte sedimentation rate—51 mm/h; C3/C4/CH50: within normal limits; B2 glycoprotein—negative; Anticardiolipin—negative; TPO: thyroperoxidase antibody—negative; thyroglobulin antibody—negative; ANCA: antineutrophil cytoplasmic antibody—negative; ACE: angiotensin converting enzyme—within normal limits; GAD 65: Glutamic acid decarboxylase—negative; NMDA: N-methyl-D-Aspartate receptor antibody—negative; AMPA: α-amino-3-hydroxy-5-methyl-4 -isoxazolepropionic acid receptor- antibody negative; TSH: thyroid stimulating hormone—within normal limits; HIV: Human immunodeficiency virus—negative; Lyme disease—negative; West Nile Virus—negative; Enterovirus- negative; Bacterial and fungal culture—negative; HSV: Herpes Simplex Virus—negative; VZV: Varicella Zoster Virus—negative; HHV6: Human Herpes Virus 6—negative; EBV: Epstein Barr Virus—negative; GFAP: Glial Fibrillary Acidic Protein—negative; LGI1: Leucine-rich glioma-inactivated—negative; CASPR2: Contactin-associated protein-like 2—negative; DPPX: dipeptidyl-peptidase-like protein 6—negative; GABA: gamma-aminobutyric acid—negative; mGlu1: metabotropic glutamate receptor 1—negative; CRMP-5: CV2/collapsin response mediator protein—negative; Voltage gated potassium channel—negative.
jcm-10-00881-t002_Table 2Table 2 Common antiseizure medications, medications utilized in hospitalized patients and associated carbohydrate, fat, and alcohol content.
Intravenous Product (General Product Concentration)
Carbohydrate Excipient and Amount Per Vial
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Brivaracetam (10 mg/mL) – – – –
Diazepam (5 mg/mL) [41] Propylene glycol: 414 mg 828 mg CHO/10 mg – 79 mg
Famotidine (10 mg/mL) [41] Mannitol: 20 mg 40 mg CHO/40 mg – –
Fosphenytoin [42] – – – –
Lorazepam (2 mg/mL) [42] Propylene glycol: 753 mg – – –
Pentobarbital (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Phenobarbital (130 mg/mL) [41] Propylene glycol: 702 mg – – 79 mg
Phenytoin (50 mg/mL) [41] Propylene glycol: 414 mg – – 79 mg
Propofol (10 mg/mL) [41] Glycerol: 22.5 mg/mL 450 mg CHO/h
(20 mL/h) Soybean oil: 100 mg/mL Benzyl alcohol *
Egg Lecithin: 12 mg/mL
Lipid: 100 mg/mL
(1.1 kcal/mL)
Ketamine (multiple) – – – –
Lacosamide (multiple) – – – –
Midazolam (multiple) – – – Benzyl alcohol †
Thiopental (25 mg/mL) – – – –
Valproate (20 mg/mL) – – – –
Trimethoprim-sulfamethoxazole (Bactrim®) diluted in Dextrose 5% W 100 mL per 80–400 mg TMP-SMX Dextrose: 5 g/100 ml Up to 20 g CHO per dose – –
Vancomycin (Vancocin®) diluted in Dextrose 5% W per 1 g/250 mL solution Dextrose: 5 g/100 ml Up to 2 g CHO per dose – –
Enteral Product § (General Product Strength)
Carbohydrate Excipient and Amount Per Unit
Carbohydrate Content at a Common Dose
Fat Content
Alcohol Content
Carbamazepine (extended-release tablet) Lactose monohydrate ‡
Microcrystalline cellulose ‡ – – –
Clobazam (10 mg tablet) [43] 105.3 mg/tablet ≈100 mg/10 mg – –
Clonazepam (0.5 mg tablet) [43] 143.5 mg/tablet ≈2800 mg/10 mg – –
Levetiracetam (immediate release tablet) Croscarmellose sodium ‡
Polyethylene glycol 3350 ‡
Polyethylene glycol 6000 ‡ – – Polyvinyl alcohol
Psyllium (Metamucil) packet 9 g CHO/tablespoon 27 g CHO/day (TID) – –
Divalproex sodium (extended-release tablet) Hypromelloses ‡
Lactose monohydrate ‡
Polyethylene glycol ‡
Propylene glycol ‡
Macrogol ‡
Microcrystalline cellulose ‡ – – n-Butyl alcohol
Isopropyl alcohol
Polyvinyl alcohol
See Appendix A for package inserts. * Present at 1.5 mg/mL in all vial sizes (0.15% w/v). Avoid use in pediatric populations due to benzyl alcohol content. † Present at 10 mg/mL in all vial sizes (1% w/v), except preservative-free formulations. Avoid use in pediatric populations due to benzyl alcohol content. ‡ Unknown amount of relative excipient may affect ketosis but is likely clinically insignificant. § Solution and suspension formulations should be avoided if possible as they usually contain sugars that will affect ketosis.
jcm-10-00881-t003_Table 3Table 3 Ketogenic Diet checklist for Status Epilepticus.
Pearls to Consider for Starting and Maintaining a Ketogenic Diet (KD)
I. KD initiation
○ Check fasting lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D serum levels
○ Record baseline weight and height
○ Continuous video EEG
○ Dietitian/nutrition consult (consider pediatric nutritionist)
○ Stop current enteral formula
○ Reduce carbohydrate content in medications and parenteral fluids with pharmacy input
○ Active communication with nursing/pharmacy, EMR warnings, and signs in room are crucial to avoid medication/IV-containing carbohydrates
○ Begin KD (e.g., KetoCal/MCT oil)
○ Include multivitamin injection, Vit. D and calcium supplementation via nasogastric tube/gastric tube
○ Change any oral agents from liquid formulation to crushed tablet formulation
II. KD maintenance
○ Remove all common carbohydrate excipients in intravenous fluids, including:
○ Glycerin
○ Maltodextrin
○ Propylene glycol
○ Sugars (dextrose, fructose, glucose, lactose, sucrose, corn syrup)
○ Sugar alcohols (glycerol, mannitol, sorbitol)
○ Starches
○
KD can be challenged via coadministration of other meds & IVs!
III. Pitfalls to consider:
○ Contraindications: unstable metabolic derangements, hemodynamic instability, coagulopathy/bleeding diathesis, pancreatitis, liver failure, severe hyperlipidemia, ileus, pregnancy, known fatty acid oxidation disorder or pyruvate carboxylase deficiency
○
Propofol infusions cannot be given within 24 h before starting a KD!
Adapted & modified from Table 3 from Thakur KT, Probasco JC, Hocker SE, et al. Neurology. 2014 Feb 25; 82(8): 665–670. [4]. | UNKNOWN DOSE | DrugDosageText | CC BY | 33671485 | 19,466,490 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood lactate dehydrogenase increased'. | Histiocytic Sarcoma: Challenging Course, Dismal Outcome.
Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution. Most commonly, it occurs as a primary malignancy. In approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated. The clinical presentation varies from a localized solitary mass to severe disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system. Systemic symptoms in terms of weight loss, fever and night sweats often occur. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma.
Introduction
Histiocytic sarcoma is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system [1,2]. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution [1,3,4,5]. Most commonly, it occurs as a primary malignancy; however, in approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated [6]. The clinical presentation varies from a localized solitary mass to a severely disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system [7]. Systemic symptoms in terms of weight loss, fever and night sweats often occur [8]. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics [7]. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months [4]. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma (Figure 1, Figure 2, Figure 3 and Figure 4).
To summarize, this case clearly demonstrates the challenging course of patients with histiocytic sarcoma. The rareness and severe complexity of HS requires a multidisciplinary and specialized approach throughout the diagnostic workout, treatment and follow-up. A rapid establishment of a correct diagnosis, staging of the disease and a personalized, aggressive treatment strategy is essential to improve outcomes in these patients. Even so, the prognosis remains extremely dismal, especially in the case of a disseminated disease at the time of diagnosis.
Author Contributions
K.F.A., L.D.S., P.K. and T.B.P. acquired and interpreted the data. K.F.A., L.D.S., P.K. and T.B.P. drafted the manuscript. K.F.A. and L.D.S. revised the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
The patient gave his written consent for the acquisition and publication of the presented data.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 A 43-year-old previously healthy male was admitted to the surgical unit by his general practitioner with suspicions of acute diverticulitis. The patient complained of constant pain in the epigastric region and under the right and left rib curvature for the previous week upon admission. The pain was intensified when bending forwards and accompanied by an unspecific feeling of fatigue. The patient reported similar symptoms three weeks prior to admission, which remitted spontaneously. Any systemic symptoms of fever, unintended weight loss or night sweats were denied. At admission, the patient had a slight tachycardia; all other vital parameters were normal. Initial laboratory data came out with an elevated C-reactive protein (CRP; 176 mg/L) and a slightly elevated total leukocyte count (9.8 × 109/L). Hepatic and renal biochemical markers were within normal ranges. On physical examination the abdomen was described as tender in the upper quadrants and around the umbilicus but without peritoneal reaction. On suspicion of an intraabdominal abscess, a computed tomography (CT) scan was performed showing free liquid surrounding the liver and the spleen as well as in the small pelvis. There was no free air. However, the upper abdomen was seen with a diffuse reaction in the fatty tissue around the pylorus and ventricle. Radiologically, a perforated ulcer was suspected. The patient underwent a diagnostic laparoscopy, revealing peritonitis in all quadrants and three liters of free fluid. There were no signs of feces, pus or bile. The greater omentum was adherent in a conglomerate consisting of the duodenum, ventricle, pancreas and transverse colon. It was not possible to get a sufficient overview of the structures laparoscopically and the procedure was converted to an explorative laparotomy revealing reactive, stearin-like changes spread in the peritoneal cavity ((A,B), white arrows). The conglomerate was dissected and the posterior part of the ventricle was inspected, revealing no ulcers. The duodenum was mobilized by the Kocher maneuver, also revealing no ulcers or perforation. Perioperatively, an esophago-gastro-duodenoscopy was performed, revealing no ulcerations or pathology. A piece of the omentum was removed for histopathological examination and an intraabdominal drain was placed before ending the procedure. The findings were suspected to be caused by pancreatitis. The postoperative course was uneventful, the drain was removed after seven days and the patient was discharged after eight days with a plan of outpatient follow-up. On postoperative day 17 he was readmitted for drainage of 3.5 L ascites, which had recollected. The pancreas was without signs of pancreatitis on a triple-phase CT. Diagnostic ultrasound described no gallstones.
Figure 2 Histopathology of omental infiltrate and ascitic fluid: (A) Omental fatty tissue with diffuse infiltration of tumor cells (HE×4). (B) The tumor cells were large with vesicular nuclei. Frequent mitoses were seen (HE×40). (C) CD68PGM1 showing characteristic granular cytoplasmic staining (×40). (D) Cytomorphology of the tumor cells in ascitic fluid (×40). A histopathological examination of the resected tissue from the omentum demonstrated a dense and diffuse infiltration of the fatty tissue by large mononuclear cells with large vesicular nuclei with eosinophilic nucleoli. The cytoplasm was eosinophilic with some vacuolization. The cells were of a hematological origin and expressed CD45. They had a fully developed histiocytic differentiation profile with an immunohistochemical expression of CD68, CD163, CD4, CD56 and lysozyme and showed a high proliferative rate that in areas reached 50% (Ki-67). The precursor cell, dendritic cell, melanocytic, neuroendocrine cell, B-cell, T-cell and Langerhans cell markers were negative. No BRAF-mutation could be demonstrated. The PD-L1 was negative. Next generation sequencing (NGS) could not demonstrate any fusions. The NGS panel used was ‘Archers FusionPlex Lymphoma’, investigating the mutation, expression and fusion of 125 genes. Ascitic fluid cytology revealed malignant cells with the same phenotype as the tumor tissue in the omentum. The findings were most compatible with histiocytic sarcoma (HS). A differential diagnosis could be monoblastic leukemia, which was excluded on the examination of bone marrow biopsies. It took 24 days from initial hospitalization until diagnosis, which was confirmed by an expert second opinion. The following day the patient was transferred to a specialized hematological department at a tertiary hospital.
Figure 3 Hybrid imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/CT (2-[18F]FDG PET/CT) was performed for the staging of the disease and as baseline for monitoring of the treatment response. Imaging performed 1 h post-injection of 4.0 MBq/kg 2-[18F]FDG showed a moderately metabolically active, irregular thickening of the peritoneal folds and extensive carcinomatosis-like infiltration in the omentum, mesentery and the pelvic cavity (A–D, yellow arrows). There was minor ascitic fluid in the abdominal and pelvic cavities. There were also metabolically active, enlarged lymph nodes in the mediastinum and upper retroperitoneum. The findings were considered highly suspicious for malignancy. At this point, plasma lactate dehydrogenase (LDH) levels, a future tumor marker in this patient, were elevated (366 U/L; reference range 105–205 U/L). An initial steroid treatment with prednisolone 100 mg/daily had a good effect on the tendency of the recollection of ascites. However, as no standardized treatment for this patient category without comorbidity exists, a hematological specialized tumor board, after consent from the patient, decided to administer a chemotherapy regimen of ifosfamide, carboplatin and etoposide (ICE), which was initiated one month after initial hospitalization. The patient tolerated the treatment well. At clinical follow-up after two cycles of ICE, the patient’s wellbeing was improved, the plasma LDH was normalized and imaging with 2-[18F]FDG PET/CT demonstrated a substantial partial response (PR), both metabolically and morphologically, of the previously described findings in the peritoneum. There were still metabolically active, carcinomatosis-like findings in the omentum, mesentery and on the liver surface (E–H, magenta arrows). There were no pathological lymph nodes. After completion of four cycles of ICE, the metabolic complete response (CR) and a further morphological PR were reported on follow-up 2-[18F]FDG PET/CT (not shown). The plasma LDH was still within a normal range. The patient tolerated the fifth and final cycle of ICE well.
Figure 4 To reduce the risk of HS relapse, an experimental therapeutic approach with high-dose chemotherapy administering a BEAM (carmustine + etoposide + cytarabine + melphalan) regimen and a subsequent autologous stem cell transplant (SCT) was initiated. The patient tolerated the treatment well and at follow-up +60 days after BEAM/SCT the regeneration of bone marrow was considered complete and the tumor marker plasma LDH was still within the reference range (157 U/L). 2-[18F]FDG PET/CT (A) demonstrated a metabolic CR and a further morphological PR. There were now relatively symmetrically localized, metabolically active lymph nodes at the right root of the neck, in both sides of the mediastinum and the lung hilum (black arrow), compatible with possible granulomatous inflammation. Two months later the patient reported a gradual worsening of bone pain in the lumbar and pelvic region. The plasma LDH was now elevated (450 U/L) and thrombocyte and hemoglobin levels were low. A relapse of HS was suspected, which was confirmed by a bone marrow biopsy that showed a massive infiltration of almost 100% of malignant histiocytic cells with blastoid morphology and an immunohistochemical profile similar to previous specimens. Findings on 2-[18F]FDG PET/CT (B) were compatible with a relapse, demonstrating a heterogeneous, pathologically increased FDG-uptake in the bone marrow in the axial and peripheral skeleton (green arrows). There were metabolically active lymph nodes above and now also below the diaphragm. A malignant bone marrow infiltration with a myeloid expansion was considered the cause of the patient’s bone pain. The plasma LDH rose rapidly to 5100 U/L and salvage therapy with an acute myelogenous leukemia regime (CLAG-M; cladribine + cytarabine + mitoxantrone) was initiated. The treatment had a good effect on the patient’s bone pain and wellbeing. The plasma LDH was normalized within days and histopathological examinations showed no tumor cells in the blood and no malignant cells in the bone marrow biopsy. 2-[18F]FDG PET/CT (C) demonstrated a metabolic PR of previously malignant findings in the bone marrow. There were now splenic lesions compatible with abscesses. A second course of CLAG-M was administered and, as the patient had achieved a second CR confirmed by a bone marrow biopsy, a non-myeloablative allogeneic SCT was considered. However, within a short period of time the patient again reported bone pain and he developed cutaneous papules on the trunk end lower extremity from which a biopsy showed HS. The plasma LDH also increased rapidly and 2-[18F]FDG PET/CT (not shown) again demonstrated progression with a pathologically increased FDG-uptake in the bone marrow and new metabolically active cutaneous lesions on the abdomen. The findings were compatible with a systemic relapse and an allogeneic SCT was now not a feasible treatment option. Palliative treatment with a modified FLAG-Ida regime (fludarabine + cytarabine + idarubicin + filgrastim) initially had a good effect on the bone pain; the cutaneous lesions regressed and the plasma LDH decreased. However, the effect was short-lived and the patient experienced intermittent fever, bone pain, fatigue and blood cell counts that demonstrated cytopenia. The plasma LDH again increased. The patient’s clinical condition worsened significantly and after short periods of treatment with high-dose cytarabine and hydroxycarbamide, further treatment attempts with intensive regimen chemotherapy were considered futile. No appropriate protocolled treatment was found suitable for the patient and the treatment aim of long term survival was abated. The patient passed away shortly after, 15 months after his initial hospitalization.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CYTARABINE, FILGRASTIM, FLUDARABINE PHOSPHATE, HYDROXYUREA, IDARUBICIN | DrugsGivenReaction | CC BY | 33671860 | 19,961,558 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bone pain'. | Histiocytic Sarcoma: Challenging Course, Dismal Outcome.
Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution. Most commonly, it occurs as a primary malignancy. In approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated. The clinical presentation varies from a localized solitary mass to severe disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system. Systemic symptoms in terms of weight loss, fever and night sweats often occur. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma.
Introduction
Histiocytic sarcoma is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system [1,2]. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution [1,3,4,5]. Most commonly, it occurs as a primary malignancy; however, in approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated [6]. The clinical presentation varies from a localized solitary mass to a severely disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system [7]. Systemic symptoms in terms of weight loss, fever and night sweats often occur [8]. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics [7]. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months [4]. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma (Figure 1, Figure 2, Figure 3 and Figure 4).
To summarize, this case clearly demonstrates the challenging course of patients with histiocytic sarcoma. The rareness and severe complexity of HS requires a multidisciplinary and specialized approach throughout the diagnostic workout, treatment and follow-up. A rapid establishment of a correct diagnosis, staging of the disease and a personalized, aggressive treatment strategy is essential to improve outcomes in these patients. Even so, the prognosis remains extremely dismal, especially in the case of a disseminated disease at the time of diagnosis.
Author Contributions
K.F.A., L.D.S., P.K. and T.B.P. acquired and interpreted the data. K.F.A., L.D.S., P.K. and T.B.P. drafted the manuscript. K.F.A. and L.D.S. revised the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
The patient gave his written consent for the acquisition and publication of the presented data.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 A 43-year-old previously healthy male was admitted to the surgical unit by his general practitioner with suspicions of acute diverticulitis. The patient complained of constant pain in the epigastric region and under the right and left rib curvature for the previous week upon admission. The pain was intensified when bending forwards and accompanied by an unspecific feeling of fatigue. The patient reported similar symptoms three weeks prior to admission, which remitted spontaneously. Any systemic symptoms of fever, unintended weight loss or night sweats were denied. At admission, the patient had a slight tachycardia; all other vital parameters were normal. Initial laboratory data came out with an elevated C-reactive protein (CRP; 176 mg/L) and a slightly elevated total leukocyte count (9.8 × 109/L). Hepatic and renal biochemical markers were within normal ranges. On physical examination the abdomen was described as tender in the upper quadrants and around the umbilicus but without peritoneal reaction. On suspicion of an intraabdominal abscess, a computed tomography (CT) scan was performed showing free liquid surrounding the liver and the spleen as well as in the small pelvis. There was no free air. However, the upper abdomen was seen with a diffuse reaction in the fatty tissue around the pylorus and ventricle. Radiologically, a perforated ulcer was suspected. The patient underwent a diagnostic laparoscopy, revealing peritonitis in all quadrants and three liters of free fluid. There were no signs of feces, pus or bile. The greater omentum was adherent in a conglomerate consisting of the duodenum, ventricle, pancreas and transverse colon. It was not possible to get a sufficient overview of the structures laparoscopically and the procedure was converted to an explorative laparotomy revealing reactive, stearin-like changes spread in the peritoneal cavity ((A,B), white arrows). The conglomerate was dissected and the posterior part of the ventricle was inspected, revealing no ulcers. The duodenum was mobilized by the Kocher maneuver, also revealing no ulcers or perforation. Perioperatively, an esophago-gastro-duodenoscopy was performed, revealing no ulcerations or pathology. A piece of the omentum was removed for histopathological examination and an intraabdominal drain was placed before ending the procedure. The findings were suspected to be caused by pancreatitis. The postoperative course was uneventful, the drain was removed after seven days and the patient was discharged after eight days with a plan of outpatient follow-up. On postoperative day 17 he was readmitted for drainage of 3.5 L ascites, which had recollected. The pancreas was without signs of pancreatitis on a triple-phase CT. Diagnostic ultrasound described no gallstones.
Figure 2 Histopathology of omental infiltrate and ascitic fluid: (A) Omental fatty tissue with diffuse infiltration of tumor cells (HE×4). (B) The tumor cells were large with vesicular nuclei. Frequent mitoses were seen (HE×40). (C) CD68PGM1 showing characteristic granular cytoplasmic staining (×40). (D) Cytomorphology of the tumor cells in ascitic fluid (×40). A histopathological examination of the resected tissue from the omentum demonstrated a dense and diffuse infiltration of the fatty tissue by large mononuclear cells with large vesicular nuclei with eosinophilic nucleoli. The cytoplasm was eosinophilic with some vacuolization. The cells were of a hematological origin and expressed CD45. They had a fully developed histiocytic differentiation profile with an immunohistochemical expression of CD68, CD163, CD4, CD56 and lysozyme and showed a high proliferative rate that in areas reached 50% (Ki-67). The precursor cell, dendritic cell, melanocytic, neuroendocrine cell, B-cell, T-cell and Langerhans cell markers were negative. No BRAF-mutation could be demonstrated. The PD-L1 was negative. Next generation sequencing (NGS) could not demonstrate any fusions. The NGS panel used was ‘Archers FusionPlex Lymphoma’, investigating the mutation, expression and fusion of 125 genes. Ascitic fluid cytology revealed malignant cells with the same phenotype as the tumor tissue in the omentum. The findings were most compatible with histiocytic sarcoma (HS). A differential diagnosis could be monoblastic leukemia, which was excluded on the examination of bone marrow biopsies. It took 24 days from initial hospitalization until diagnosis, which was confirmed by an expert second opinion. The following day the patient was transferred to a specialized hematological department at a tertiary hospital.
Figure 3 Hybrid imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/CT (2-[18F]FDG PET/CT) was performed for the staging of the disease and as baseline for monitoring of the treatment response. Imaging performed 1 h post-injection of 4.0 MBq/kg 2-[18F]FDG showed a moderately metabolically active, irregular thickening of the peritoneal folds and extensive carcinomatosis-like infiltration in the omentum, mesentery and the pelvic cavity (A–D, yellow arrows). There was minor ascitic fluid in the abdominal and pelvic cavities. There were also metabolically active, enlarged lymph nodes in the mediastinum and upper retroperitoneum. The findings were considered highly suspicious for malignancy. At this point, plasma lactate dehydrogenase (LDH) levels, a future tumor marker in this patient, were elevated (366 U/L; reference range 105–205 U/L). An initial steroid treatment with prednisolone 100 mg/daily had a good effect on the tendency of the recollection of ascites. However, as no standardized treatment for this patient category without comorbidity exists, a hematological specialized tumor board, after consent from the patient, decided to administer a chemotherapy regimen of ifosfamide, carboplatin and etoposide (ICE), which was initiated one month after initial hospitalization. The patient tolerated the treatment well. At clinical follow-up after two cycles of ICE, the patient’s wellbeing was improved, the plasma LDH was normalized and imaging with 2-[18F]FDG PET/CT demonstrated a substantial partial response (PR), both metabolically and morphologically, of the previously described findings in the peritoneum. There were still metabolically active, carcinomatosis-like findings in the omentum, mesentery and on the liver surface (E–H, magenta arrows). There were no pathological lymph nodes. After completion of four cycles of ICE, the metabolic complete response (CR) and a further morphological PR were reported on follow-up 2-[18F]FDG PET/CT (not shown). The plasma LDH was still within a normal range. The patient tolerated the fifth and final cycle of ICE well.
Figure 4 To reduce the risk of HS relapse, an experimental therapeutic approach with high-dose chemotherapy administering a BEAM (carmustine + etoposide + cytarabine + melphalan) regimen and a subsequent autologous stem cell transplant (SCT) was initiated. The patient tolerated the treatment well and at follow-up +60 days after BEAM/SCT the regeneration of bone marrow was considered complete and the tumor marker plasma LDH was still within the reference range (157 U/L). 2-[18F]FDG PET/CT (A) demonstrated a metabolic CR and a further morphological PR. There were now relatively symmetrically localized, metabolically active lymph nodes at the right root of the neck, in both sides of the mediastinum and the lung hilum (black arrow), compatible with possible granulomatous inflammation. Two months later the patient reported a gradual worsening of bone pain in the lumbar and pelvic region. The plasma LDH was now elevated (450 U/L) and thrombocyte and hemoglobin levels were low. A relapse of HS was suspected, which was confirmed by a bone marrow biopsy that showed a massive infiltration of almost 100% of malignant histiocytic cells with blastoid morphology and an immunohistochemical profile similar to previous specimens. Findings on 2-[18F]FDG PET/CT (B) were compatible with a relapse, demonstrating a heterogeneous, pathologically increased FDG-uptake in the bone marrow in the axial and peripheral skeleton (green arrows). There were metabolically active lymph nodes above and now also below the diaphragm. A malignant bone marrow infiltration with a myeloid expansion was considered the cause of the patient’s bone pain. The plasma LDH rose rapidly to 5100 U/L and salvage therapy with an acute myelogenous leukemia regime (CLAG-M; cladribine + cytarabine + mitoxantrone) was initiated. The treatment had a good effect on the patient’s bone pain and wellbeing. The plasma LDH was normalized within days and histopathological examinations showed no tumor cells in the blood and no malignant cells in the bone marrow biopsy. 2-[18F]FDG PET/CT (C) demonstrated a metabolic PR of previously malignant findings in the bone marrow. There were now splenic lesions compatible with abscesses. A second course of CLAG-M was administered and, as the patient had achieved a second CR confirmed by a bone marrow biopsy, a non-myeloablative allogeneic SCT was considered. However, within a short period of time the patient again reported bone pain and he developed cutaneous papules on the trunk end lower extremity from which a biopsy showed HS. The plasma LDH also increased rapidly and 2-[18F]FDG PET/CT (not shown) again demonstrated progression with a pathologically increased FDG-uptake in the bone marrow and new metabolically active cutaneous lesions on the abdomen. The findings were compatible with a systemic relapse and an allogeneic SCT was now not a feasible treatment option. Palliative treatment with a modified FLAG-Ida regime (fludarabine + cytarabine + idarubicin + filgrastim) initially had a good effect on the bone pain; the cutaneous lesions regressed and the plasma LDH decreased. However, the effect was short-lived and the patient experienced intermittent fever, bone pain, fatigue and blood cell counts that demonstrated cytopenia. The plasma LDH again increased. The patient’s clinical condition worsened significantly and after short periods of treatment with high-dose cytarabine and hydroxycarbamide, further treatment attempts with intensive regimen chemotherapy were considered futile. No appropriate protocolled treatment was found suitable for the patient and the treatment aim of long term survival was abated. The patient passed away shortly after, 15 months after his initial hospitalization.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CYTARABINE, FILGRASTIM, FLUDARABINE PHOSPHATE, HYDROXYUREA, IDARUBICIN | DrugsGivenReaction | CC BY | 33671860 | 19,961,558 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Histiocytic Sarcoma: Challenging Course, Dismal Outcome.
Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution. Most commonly, it occurs as a primary malignancy. In approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated. The clinical presentation varies from a localized solitary mass to severe disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system. Systemic symptoms in terms of weight loss, fever and night sweats often occur. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma.
Introduction
Histiocytic sarcoma is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system [1,2]. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution [1,3,4,5]. Most commonly, it occurs as a primary malignancy; however, in approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated [6]. The clinical presentation varies from a localized solitary mass to a severely disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system [7]. Systemic symptoms in terms of weight loss, fever and night sweats often occur [8]. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics [7]. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months [4]. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma (Figure 1, Figure 2, Figure 3 and Figure 4).
To summarize, this case clearly demonstrates the challenging course of patients with histiocytic sarcoma. The rareness and severe complexity of HS requires a multidisciplinary and specialized approach throughout the diagnostic workout, treatment and follow-up. A rapid establishment of a correct diagnosis, staging of the disease and a personalized, aggressive treatment strategy is essential to improve outcomes in these patients. Even so, the prognosis remains extremely dismal, especially in the case of a disseminated disease at the time of diagnosis.
Author Contributions
K.F.A., L.D.S., P.K. and T.B.P. acquired and interpreted the data. K.F.A., L.D.S., P.K. and T.B.P. drafted the manuscript. K.F.A. and L.D.S. revised the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
The patient gave his written consent for the acquisition and publication of the presented data.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 A 43-year-old previously healthy male was admitted to the surgical unit by his general practitioner with suspicions of acute diverticulitis. The patient complained of constant pain in the epigastric region and under the right and left rib curvature for the previous week upon admission. The pain was intensified when bending forwards and accompanied by an unspecific feeling of fatigue. The patient reported similar symptoms three weeks prior to admission, which remitted spontaneously. Any systemic symptoms of fever, unintended weight loss or night sweats were denied. At admission, the patient had a slight tachycardia; all other vital parameters were normal. Initial laboratory data came out with an elevated C-reactive protein (CRP; 176 mg/L) and a slightly elevated total leukocyte count (9.8 × 109/L). Hepatic and renal biochemical markers were within normal ranges. On physical examination the abdomen was described as tender in the upper quadrants and around the umbilicus but without peritoneal reaction. On suspicion of an intraabdominal abscess, a computed tomography (CT) scan was performed showing free liquid surrounding the liver and the spleen as well as in the small pelvis. There was no free air. However, the upper abdomen was seen with a diffuse reaction in the fatty tissue around the pylorus and ventricle. Radiologically, a perforated ulcer was suspected. The patient underwent a diagnostic laparoscopy, revealing peritonitis in all quadrants and three liters of free fluid. There were no signs of feces, pus or bile. The greater omentum was adherent in a conglomerate consisting of the duodenum, ventricle, pancreas and transverse colon. It was not possible to get a sufficient overview of the structures laparoscopically and the procedure was converted to an explorative laparotomy revealing reactive, stearin-like changes spread in the peritoneal cavity ((A,B), white arrows). The conglomerate was dissected and the posterior part of the ventricle was inspected, revealing no ulcers. The duodenum was mobilized by the Kocher maneuver, also revealing no ulcers or perforation. Perioperatively, an esophago-gastro-duodenoscopy was performed, revealing no ulcerations or pathology. A piece of the omentum was removed for histopathological examination and an intraabdominal drain was placed before ending the procedure. The findings were suspected to be caused by pancreatitis. The postoperative course was uneventful, the drain was removed after seven days and the patient was discharged after eight days with a plan of outpatient follow-up. On postoperative day 17 he was readmitted for drainage of 3.5 L ascites, which had recollected. The pancreas was without signs of pancreatitis on a triple-phase CT. Diagnostic ultrasound described no gallstones.
Figure 2 Histopathology of omental infiltrate and ascitic fluid: (A) Omental fatty tissue with diffuse infiltration of tumor cells (HE×4). (B) The tumor cells were large with vesicular nuclei. Frequent mitoses were seen (HE×40). (C) CD68PGM1 showing characteristic granular cytoplasmic staining (×40). (D) Cytomorphology of the tumor cells in ascitic fluid (×40). A histopathological examination of the resected tissue from the omentum demonstrated a dense and diffuse infiltration of the fatty tissue by large mononuclear cells with large vesicular nuclei with eosinophilic nucleoli. The cytoplasm was eosinophilic with some vacuolization. The cells were of a hematological origin and expressed CD45. They had a fully developed histiocytic differentiation profile with an immunohistochemical expression of CD68, CD163, CD4, CD56 and lysozyme and showed a high proliferative rate that in areas reached 50% (Ki-67). The precursor cell, dendritic cell, melanocytic, neuroendocrine cell, B-cell, T-cell and Langerhans cell markers were negative. No BRAF-mutation could be demonstrated. The PD-L1 was negative. Next generation sequencing (NGS) could not demonstrate any fusions. The NGS panel used was ‘Archers FusionPlex Lymphoma’, investigating the mutation, expression and fusion of 125 genes. Ascitic fluid cytology revealed malignant cells with the same phenotype as the tumor tissue in the omentum. The findings were most compatible with histiocytic sarcoma (HS). A differential diagnosis could be monoblastic leukemia, which was excluded on the examination of bone marrow biopsies. It took 24 days from initial hospitalization until diagnosis, which was confirmed by an expert second opinion. The following day the patient was transferred to a specialized hematological department at a tertiary hospital.
Figure 3 Hybrid imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/CT (2-[18F]FDG PET/CT) was performed for the staging of the disease and as baseline for monitoring of the treatment response. Imaging performed 1 h post-injection of 4.0 MBq/kg 2-[18F]FDG showed a moderately metabolically active, irregular thickening of the peritoneal folds and extensive carcinomatosis-like infiltration in the omentum, mesentery and the pelvic cavity (A–D, yellow arrows). There was minor ascitic fluid in the abdominal and pelvic cavities. There were also metabolically active, enlarged lymph nodes in the mediastinum and upper retroperitoneum. The findings were considered highly suspicious for malignancy. At this point, plasma lactate dehydrogenase (LDH) levels, a future tumor marker in this patient, were elevated (366 U/L; reference range 105–205 U/L). An initial steroid treatment with prednisolone 100 mg/daily had a good effect on the tendency of the recollection of ascites. However, as no standardized treatment for this patient category without comorbidity exists, a hematological specialized tumor board, after consent from the patient, decided to administer a chemotherapy regimen of ifosfamide, carboplatin and etoposide (ICE), which was initiated one month after initial hospitalization. The patient tolerated the treatment well. At clinical follow-up after two cycles of ICE, the patient’s wellbeing was improved, the plasma LDH was normalized and imaging with 2-[18F]FDG PET/CT demonstrated a substantial partial response (PR), both metabolically and morphologically, of the previously described findings in the peritoneum. There were still metabolically active, carcinomatosis-like findings in the omentum, mesentery and on the liver surface (E–H, magenta arrows). There were no pathological lymph nodes. After completion of four cycles of ICE, the metabolic complete response (CR) and a further morphological PR were reported on follow-up 2-[18F]FDG PET/CT (not shown). The plasma LDH was still within a normal range. The patient tolerated the fifth and final cycle of ICE well.
Figure 4 To reduce the risk of HS relapse, an experimental therapeutic approach with high-dose chemotherapy administering a BEAM (carmustine + etoposide + cytarabine + melphalan) regimen and a subsequent autologous stem cell transplant (SCT) was initiated. The patient tolerated the treatment well and at follow-up +60 days after BEAM/SCT the regeneration of bone marrow was considered complete and the tumor marker plasma LDH was still within the reference range (157 U/L). 2-[18F]FDG PET/CT (A) demonstrated a metabolic CR and a further morphological PR. There were now relatively symmetrically localized, metabolically active lymph nodes at the right root of the neck, in both sides of the mediastinum and the lung hilum (black arrow), compatible with possible granulomatous inflammation. Two months later the patient reported a gradual worsening of bone pain in the lumbar and pelvic region. The plasma LDH was now elevated (450 U/L) and thrombocyte and hemoglobin levels were low. A relapse of HS was suspected, which was confirmed by a bone marrow biopsy that showed a massive infiltration of almost 100% of malignant histiocytic cells with blastoid morphology and an immunohistochemical profile similar to previous specimens. Findings on 2-[18F]FDG PET/CT (B) were compatible with a relapse, demonstrating a heterogeneous, pathologically increased FDG-uptake in the bone marrow in the axial and peripheral skeleton (green arrows). There were metabolically active lymph nodes above and now also below the diaphragm. A malignant bone marrow infiltration with a myeloid expansion was considered the cause of the patient’s bone pain. The plasma LDH rose rapidly to 5100 U/L and salvage therapy with an acute myelogenous leukemia regime (CLAG-M; cladribine + cytarabine + mitoxantrone) was initiated. The treatment had a good effect on the patient’s bone pain and wellbeing. The plasma LDH was normalized within days and histopathological examinations showed no tumor cells in the blood and no malignant cells in the bone marrow biopsy. 2-[18F]FDG PET/CT (C) demonstrated a metabolic PR of previously malignant findings in the bone marrow. There were now splenic lesions compatible with abscesses. A second course of CLAG-M was administered and, as the patient had achieved a second CR confirmed by a bone marrow biopsy, a non-myeloablative allogeneic SCT was considered. However, within a short period of time the patient again reported bone pain and he developed cutaneous papules on the trunk end lower extremity from which a biopsy showed HS. The plasma LDH also increased rapidly and 2-[18F]FDG PET/CT (not shown) again demonstrated progression with a pathologically increased FDG-uptake in the bone marrow and new metabolically active cutaneous lesions on the abdomen. The findings were compatible with a systemic relapse and an allogeneic SCT was now not a feasible treatment option. Palliative treatment with a modified FLAG-Ida regime (fludarabine + cytarabine + idarubicin + filgrastim) initially had a good effect on the bone pain; the cutaneous lesions regressed and the plasma LDH decreased. However, the effect was short-lived and the patient experienced intermittent fever, bone pain, fatigue and blood cell counts that demonstrated cytopenia. The plasma LDH again increased. The patient’s clinical condition worsened significantly and after short periods of treatment with high-dose cytarabine and hydroxycarbamide, further treatment attempts with intensive regimen chemotherapy were considered futile. No appropriate protocolled treatment was found suitable for the patient and the treatment aim of long term survival was abated. The patient passed away shortly after, 15 months after his initial hospitalization.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CYTARABINE, FILGRASTIM, FLUDARABINE PHOSPHATE, HYDROXYUREA, IDARUBICIN | DrugsGivenReaction | CC BY | 33671860 | 19,961,558 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytopenia'. | Histiocytic Sarcoma: Challenging Course, Dismal Outcome.
Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution. Most commonly, it occurs as a primary malignancy. In approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated. The clinical presentation varies from a localized solitary mass to severe disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system. Systemic symptoms in terms of weight loss, fever and night sweats often occur. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma.
Introduction
Histiocytic sarcoma is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system [1,2]. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution [1,3,4,5]. Most commonly, it occurs as a primary malignancy; however, in approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated [6]. The clinical presentation varies from a localized solitary mass to a severely disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system [7]. Systemic symptoms in terms of weight loss, fever and night sweats often occur [8]. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics [7]. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months [4]. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma (Figure 1, Figure 2, Figure 3 and Figure 4).
To summarize, this case clearly demonstrates the challenging course of patients with histiocytic sarcoma. The rareness and severe complexity of HS requires a multidisciplinary and specialized approach throughout the diagnostic workout, treatment and follow-up. A rapid establishment of a correct diagnosis, staging of the disease and a personalized, aggressive treatment strategy is essential to improve outcomes in these patients. Even so, the prognosis remains extremely dismal, especially in the case of a disseminated disease at the time of diagnosis.
Author Contributions
K.F.A., L.D.S., P.K. and T.B.P. acquired and interpreted the data. K.F.A., L.D.S., P.K. and T.B.P. drafted the manuscript. K.F.A. and L.D.S. revised the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
The patient gave his written consent for the acquisition and publication of the presented data.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 A 43-year-old previously healthy male was admitted to the surgical unit by his general practitioner with suspicions of acute diverticulitis. The patient complained of constant pain in the epigastric region and under the right and left rib curvature for the previous week upon admission. The pain was intensified when bending forwards and accompanied by an unspecific feeling of fatigue. The patient reported similar symptoms three weeks prior to admission, which remitted spontaneously. Any systemic symptoms of fever, unintended weight loss or night sweats were denied. At admission, the patient had a slight tachycardia; all other vital parameters were normal. Initial laboratory data came out with an elevated C-reactive protein (CRP; 176 mg/L) and a slightly elevated total leukocyte count (9.8 × 109/L). Hepatic and renal biochemical markers were within normal ranges. On physical examination the abdomen was described as tender in the upper quadrants and around the umbilicus but without peritoneal reaction. On suspicion of an intraabdominal abscess, a computed tomography (CT) scan was performed showing free liquid surrounding the liver and the spleen as well as in the small pelvis. There was no free air. However, the upper abdomen was seen with a diffuse reaction in the fatty tissue around the pylorus and ventricle. Radiologically, a perforated ulcer was suspected. The patient underwent a diagnostic laparoscopy, revealing peritonitis in all quadrants and three liters of free fluid. There were no signs of feces, pus or bile. The greater omentum was adherent in a conglomerate consisting of the duodenum, ventricle, pancreas and transverse colon. It was not possible to get a sufficient overview of the structures laparoscopically and the procedure was converted to an explorative laparotomy revealing reactive, stearin-like changes spread in the peritoneal cavity ((A,B), white arrows). The conglomerate was dissected and the posterior part of the ventricle was inspected, revealing no ulcers. The duodenum was mobilized by the Kocher maneuver, also revealing no ulcers or perforation. Perioperatively, an esophago-gastro-duodenoscopy was performed, revealing no ulcerations or pathology. A piece of the omentum was removed for histopathological examination and an intraabdominal drain was placed before ending the procedure. The findings were suspected to be caused by pancreatitis. The postoperative course was uneventful, the drain was removed after seven days and the patient was discharged after eight days with a plan of outpatient follow-up. On postoperative day 17 he was readmitted for drainage of 3.5 L ascites, which had recollected. The pancreas was without signs of pancreatitis on a triple-phase CT. Diagnostic ultrasound described no gallstones.
Figure 2 Histopathology of omental infiltrate and ascitic fluid: (A) Omental fatty tissue with diffuse infiltration of tumor cells (HE×4). (B) The tumor cells were large with vesicular nuclei. Frequent mitoses were seen (HE×40). (C) CD68PGM1 showing characteristic granular cytoplasmic staining (×40). (D) Cytomorphology of the tumor cells in ascitic fluid (×40). A histopathological examination of the resected tissue from the omentum demonstrated a dense and diffuse infiltration of the fatty tissue by large mononuclear cells with large vesicular nuclei with eosinophilic nucleoli. The cytoplasm was eosinophilic with some vacuolization. The cells were of a hematological origin and expressed CD45. They had a fully developed histiocytic differentiation profile with an immunohistochemical expression of CD68, CD163, CD4, CD56 and lysozyme and showed a high proliferative rate that in areas reached 50% (Ki-67). The precursor cell, dendritic cell, melanocytic, neuroendocrine cell, B-cell, T-cell and Langerhans cell markers were negative. No BRAF-mutation could be demonstrated. The PD-L1 was negative. Next generation sequencing (NGS) could not demonstrate any fusions. The NGS panel used was ‘Archers FusionPlex Lymphoma’, investigating the mutation, expression and fusion of 125 genes. Ascitic fluid cytology revealed malignant cells with the same phenotype as the tumor tissue in the omentum. The findings were most compatible with histiocytic sarcoma (HS). A differential diagnosis could be monoblastic leukemia, which was excluded on the examination of bone marrow biopsies. It took 24 days from initial hospitalization until diagnosis, which was confirmed by an expert second opinion. The following day the patient was transferred to a specialized hematological department at a tertiary hospital.
Figure 3 Hybrid imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/CT (2-[18F]FDG PET/CT) was performed for the staging of the disease and as baseline for monitoring of the treatment response. Imaging performed 1 h post-injection of 4.0 MBq/kg 2-[18F]FDG showed a moderately metabolically active, irregular thickening of the peritoneal folds and extensive carcinomatosis-like infiltration in the omentum, mesentery and the pelvic cavity (A–D, yellow arrows). There was minor ascitic fluid in the abdominal and pelvic cavities. There were also metabolically active, enlarged lymph nodes in the mediastinum and upper retroperitoneum. The findings were considered highly suspicious for malignancy. At this point, plasma lactate dehydrogenase (LDH) levels, a future tumor marker in this patient, were elevated (366 U/L; reference range 105–205 U/L). An initial steroid treatment with prednisolone 100 mg/daily had a good effect on the tendency of the recollection of ascites. However, as no standardized treatment for this patient category without comorbidity exists, a hematological specialized tumor board, after consent from the patient, decided to administer a chemotherapy regimen of ifosfamide, carboplatin and etoposide (ICE), which was initiated one month after initial hospitalization. The patient tolerated the treatment well. At clinical follow-up after two cycles of ICE, the patient’s wellbeing was improved, the plasma LDH was normalized and imaging with 2-[18F]FDG PET/CT demonstrated a substantial partial response (PR), both metabolically and morphologically, of the previously described findings in the peritoneum. There were still metabolically active, carcinomatosis-like findings in the omentum, mesentery and on the liver surface (E–H, magenta arrows). There were no pathological lymph nodes. After completion of four cycles of ICE, the metabolic complete response (CR) and a further morphological PR were reported on follow-up 2-[18F]FDG PET/CT (not shown). The plasma LDH was still within a normal range. The patient tolerated the fifth and final cycle of ICE well.
Figure 4 To reduce the risk of HS relapse, an experimental therapeutic approach with high-dose chemotherapy administering a BEAM (carmustine + etoposide + cytarabine + melphalan) regimen and a subsequent autologous stem cell transplant (SCT) was initiated. The patient tolerated the treatment well and at follow-up +60 days after BEAM/SCT the regeneration of bone marrow was considered complete and the tumor marker plasma LDH was still within the reference range (157 U/L). 2-[18F]FDG PET/CT (A) demonstrated a metabolic CR and a further morphological PR. There were now relatively symmetrically localized, metabolically active lymph nodes at the right root of the neck, in both sides of the mediastinum and the lung hilum (black arrow), compatible with possible granulomatous inflammation. Two months later the patient reported a gradual worsening of bone pain in the lumbar and pelvic region. The plasma LDH was now elevated (450 U/L) and thrombocyte and hemoglobin levels were low. A relapse of HS was suspected, which was confirmed by a bone marrow biopsy that showed a massive infiltration of almost 100% of malignant histiocytic cells with blastoid morphology and an immunohistochemical profile similar to previous specimens. Findings on 2-[18F]FDG PET/CT (B) were compatible with a relapse, demonstrating a heterogeneous, pathologically increased FDG-uptake in the bone marrow in the axial and peripheral skeleton (green arrows). There were metabolically active lymph nodes above and now also below the diaphragm. A malignant bone marrow infiltration with a myeloid expansion was considered the cause of the patient’s bone pain. The plasma LDH rose rapidly to 5100 U/L and salvage therapy with an acute myelogenous leukemia regime (CLAG-M; cladribine + cytarabine + mitoxantrone) was initiated. The treatment had a good effect on the patient’s bone pain and wellbeing. The plasma LDH was normalized within days and histopathological examinations showed no tumor cells in the blood and no malignant cells in the bone marrow biopsy. 2-[18F]FDG PET/CT (C) demonstrated a metabolic PR of previously malignant findings in the bone marrow. There were now splenic lesions compatible with abscesses. A second course of CLAG-M was administered and, as the patient had achieved a second CR confirmed by a bone marrow biopsy, a non-myeloablative allogeneic SCT was considered. However, within a short period of time the patient again reported bone pain and he developed cutaneous papules on the trunk end lower extremity from which a biopsy showed HS. The plasma LDH also increased rapidly and 2-[18F]FDG PET/CT (not shown) again demonstrated progression with a pathologically increased FDG-uptake in the bone marrow and new metabolically active cutaneous lesions on the abdomen. The findings were compatible with a systemic relapse and an allogeneic SCT was now not a feasible treatment option. Palliative treatment with a modified FLAG-Ida regime (fludarabine + cytarabine + idarubicin + filgrastim) initially had a good effect on the bone pain; the cutaneous lesions regressed and the plasma LDH decreased. However, the effect was short-lived and the patient experienced intermittent fever, bone pain, fatigue and blood cell counts that demonstrated cytopenia. The plasma LDH again increased. The patient’s clinical condition worsened significantly and after short periods of treatment with high-dose cytarabine and hydroxycarbamide, further treatment attempts with intensive regimen chemotherapy were considered futile. No appropriate protocolled treatment was found suitable for the patient and the treatment aim of long term survival was abated. The patient passed away shortly after, 15 months after his initial hospitalization.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CYTARABINE, FILGRASTIM, FLUDARABINE PHOSPHATE, HYDROXYUREA, IDARUBICIN | DrugsGivenReaction | CC BY | 33671860 | 19,961,558 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'. | Histiocytic Sarcoma: Challenging Course, Dismal Outcome.
Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution. Most commonly, it occurs as a primary malignancy. In approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated. The clinical presentation varies from a localized solitary mass to severe disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system. Systemic symptoms in terms of weight loss, fever and night sweats often occur. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma.
Introduction
Histiocytic sarcoma is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system [1,2]. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution [1,3,4,5]. Most commonly, it occurs as a primary malignancy; however, in approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated [6]. The clinical presentation varies from a localized solitary mass to a severely disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system [7]. Systemic symptoms in terms of weight loss, fever and night sweats often occur [8]. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics [7]. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months [4]. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma (Figure 1, Figure 2, Figure 3 and Figure 4).
To summarize, this case clearly demonstrates the challenging course of patients with histiocytic sarcoma. The rareness and severe complexity of HS requires a multidisciplinary and specialized approach throughout the diagnostic workout, treatment and follow-up. A rapid establishment of a correct diagnosis, staging of the disease and a personalized, aggressive treatment strategy is essential to improve outcomes in these patients. Even so, the prognosis remains extremely dismal, especially in the case of a disseminated disease at the time of diagnosis.
Author Contributions
K.F.A., L.D.S., P.K. and T.B.P. acquired and interpreted the data. K.F.A., L.D.S., P.K. and T.B.P. drafted the manuscript. K.F.A. and L.D.S. revised the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
The patient gave his written consent for the acquisition and publication of the presented data.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 A 43-year-old previously healthy male was admitted to the surgical unit by his general practitioner with suspicions of acute diverticulitis. The patient complained of constant pain in the epigastric region and under the right and left rib curvature for the previous week upon admission. The pain was intensified when bending forwards and accompanied by an unspecific feeling of fatigue. The patient reported similar symptoms three weeks prior to admission, which remitted spontaneously. Any systemic symptoms of fever, unintended weight loss or night sweats were denied. At admission, the patient had a slight tachycardia; all other vital parameters were normal. Initial laboratory data came out with an elevated C-reactive protein (CRP; 176 mg/L) and a slightly elevated total leukocyte count (9.8 × 109/L). Hepatic and renal biochemical markers were within normal ranges. On physical examination the abdomen was described as tender in the upper quadrants and around the umbilicus but without peritoneal reaction. On suspicion of an intraabdominal abscess, a computed tomography (CT) scan was performed showing free liquid surrounding the liver and the spleen as well as in the small pelvis. There was no free air. However, the upper abdomen was seen with a diffuse reaction in the fatty tissue around the pylorus and ventricle. Radiologically, a perforated ulcer was suspected. The patient underwent a diagnostic laparoscopy, revealing peritonitis in all quadrants and three liters of free fluid. There were no signs of feces, pus or bile. The greater omentum was adherent in a conglomerate consisting of the duodenum, ventricle, pancreas and transverse colon. It was not possible to get a sufficient overview of the structures laparoscopically and the procedure was converted to an explorative laparotomy revealing reactive, stearin-like changes spread in the peritoneal cavity ((A,B), white arrows). The conglomerate was dissected and the posterior part of the ventricle was inspected, revealing no ulcers. The duodenum was mobilized by the Kocher maneuver, also revealing no ulcers or perforation. Perioperatively, an esophago-gastro-duodenoscopy was performed, revealing no ulcerations or pathology. A piece of the omentum was removed for histopathological examination and an intraabdominal drain was placed before ending the procedure. The findings were suspected to be caused by pancreatitis. The postoperative course was uneventful, the drain was removed after seven days and the patient was discharged after eight days with a plan of outpatient follow-up. On postoperative day 17 he was readmitted for drainage of 3.5 L ascites, which had recollected. The pancreas was without signs of pancreatitis on a triple-phase CT. Diagnostic ultrasound described no gallstones.
Figure 2 Histopathology of omental infiltrate and ascitic fluid: (A) Omental fatty tissue with diffuse infiltration of tumor cells (HE×4). (B) The tumor cells were large with vesicular nuclei. Frequent mitoses were seen (HE×40). (C) CD68PGM1 showing characteristic granular cytoplasmic staining (×40). (D) Cytomorphology of the tumor cells in ascitic fluid (×40). A histopathological examination of the resected tissue from the omentum demonstrated a dense and diffuse infiltration of the fatty tissue by large mononuclear cells with large vesicular nuclei with eosinophilic nucleoli. The cytoplasm was eosinophilic with some vacuolization. The cells were of a hematological origin and expressed CD45. They had a fully developed histiocytic differentiation profile with an immunohistochemical expression of CD68, CD163, CD4, CD56 and lysozyme and showed a high proliferative rate that in areas reached 50% (Ki-67). The precursor cell, dendritic cell, melanocytic, neuroendocrine cell, B-cell, T-cell and Langerhans cell markers were negative. No BRAF-mutation could be demonstrated. The PD-L1 was negative. Next generation sequencing (NGS) could not demonstrate any fusions. The NGS panel used was ‘Archers FusionPlex Lymphoma’, investigating the mutation, expression and fusion of 125 genes. Ascitic fluid cytology revealed malignant cells with the same phenotype as the tumor tissue in the omentum. The findings were most compatible with histiocytic sarcoma (HS). A differential diagnosis could be monoblastic leukemia, which was excluded on the examination of bone marrow biopsies. It took 24 days from initial hospitalization until diagnosis, which was confirmed by an expert second opinion. The following day the patient was transferred to a specialized hematological department at a tertiary hospital.
Figure 3 Hybrid imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/CT (2-[18F]FDG PET/CT) was performed for the staging of the disease and as baseline for monitoring of the treatment response. Imaging performed 1 h post-injection of 4.0 MBq/kg 2-[18F]FDG showed a moderately metabolically active, irregular thickening of the peritoneal folds and extensive carcinomatosis-like infiltration in the omentum, mesentery and the pelvic cavity (A–D, yellow arrows). There was minor ascitic fluid in the abdominal and pelvic cavities. There were also metabolically active, enlarged lymph nodes in the mediastinum and upper retroperitoneum. The findings were considered highly suspicious for malignancy. At this point, plasma lactate dehydrogenase (LDH) levels, a future tumor marker in this patient, were elevated (366 U/L; reference range 105–205 U/L). An initial steroid treatment with prednisolone 100 mg/daily had a good effect on the tendency of the recollection of ascites. However, as no standardized treatment for this patient category without comorbidity exists, a hematological specialized tumor board, after consent from the patient, decided to administer a chemotherapy regimen of ifosfamide, carboplatin and etoposide (ICE), which was initiated one month after initial hospitalization. The patient tolerated the treatment well. At clinical follow-up after two cycles of ICE, the patient’s wellbeing was improved, the plasma LDH was normalized and imaging with 2-[18F]FDG PET/CT demonstrated a substantial partial response (PR), both metabolically and morphologically, of the previously described findings in the peritoneum. There were still metabolically active, carcinomatosis-like findings in the omentum, mesentery and on the liver surface (E–H, magenta arrows). There were no pathological lymph nodes. After completion of four cycles of ICE, the metabolic complete response (CR) and a further morphological PR were reported on follow-up 2-[18F]FDG PET/CT (not shown). The plasma LDH was still within a normal range. The patient tolerated the fifth and final cycle of ICE well.
Figure 4 To reduce the risk of HS relapse, an experimental therapeutic approach with high-dose chemotherapy administering a BEAM (carmustine + etoposide + cytarabine + melphalan) regimen and a subsequent autologous stem cell transplant (SCT) was initiated. The patient tolerated the treatment well and at follow-up +60 days after BEAM/SCT the regeneration of bone marrow was considered complete and the tumor marker plasma LDH was still within the reference range (157 U/L). 2-[18F]FDG PET/CT (A) demonstrated a metabolic CR and a further morphological PR. There were now relatively symmetrically localized, metabolically active lymph nodes at the right root of the neck, in both sides of the mediastinum and the lung hilum (black arrow), compatible with possible granulomatous inflammation. Two months later the patient reported a gradual worsening of bone pain in the lumbar and pelvic region. The plasma LDH was now elevated (450 U/L) and thrombocyte and hemoglobin levels were low. A relapse of HS was suspected, which was confirmed by a bone marrow biopsy that showed a massive infiltration of almost 100% of malignant histiocytic cells with blastoid morphology and an immunohistochemical profile similar to previous specimens. Findings on 2-[18F]FDG PET/CT (B) were compatible with a relapse, demonstrating a heterogeneous, pathologically increased FDG-uptake in the bone marrow in the axial and peripheral skeleton (green arrows). There were metabolically active lymph nodes above and now also below the diaphragm. A malignant bone marrow infiltration with a myeloid expansion was considered the cause of the patient’s bone pain. The plasma LDH rose rapidly to 5100 U/L and salvage therapy with an acute myelogenous leukemia regime (CLAG-M; cladribine + cytarabine + mitoxantrone) was initiated. The treatment had a good effect on the patient’s bone pain and wellbeing. The plasma LDH was normalized within days and histopathological examinations showed no tumor cells in the blood and no malignant cells in the bone marrow biopsy. 2-[18F]FDG PET/CT (C) demonstrated a metabolic PR of previously malignant findings in the bone marrow. There were now splenic lesions compatible with abscesses. A second course of CLAG-M was administered and, as the patient had achieved a second CR confirmed by a bone marrow biopsy, a non-myeloablative allogeneic SCT was considered. However, within a short period of time the patient again reported bone pain and he developed cutaneous papules on the trunk end lower extremity from which a biopsy showed HS. The plasma LDH also increased rapidly and 2-[18F]FDG PET/CT (not shown) again demonstrated progression with a pathologically increased FDG-uptake in the bone marrow and new metabolically active cutaneous lesions on the abdomen. The findings were compatible with a systemic relapse and an allogeneic SCT was now not a feasible treatment option. Palliative treatment with a modified FLAG-Ida regime (fludarabine + cytarabine + idarubicin + filgrastim) initially had a good effect on the bone pain; the cutaneous lesions regressed and the plasma LDH decreased. However, the effect was short-lived and the patient experienced intermittent fever, bone pain, fatigue and blood cell counts that demonstrated cytopenia. The plasma LDH again increased. The patient’s clinical condition worsened significantly and after short periods of treatment with high-dose cytarabine and hydroxycarbamide, further treatment attempts with intensive regimen chemotherapy were considered futile. No appropriate protocolled treatment was found suitable for the patient and the treatment aim of long term survival was abated. The patient passed away shortly after, 15 months after his initial hospitalization.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CYTARABINE, FILGRASTIM, FLUDARABINE PHOSPHATE, HYDROXYUREA, IDARUBICIN | DrugsGivenReaction | CC BY | 33671860 | 19,961,558 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Histiocytic Sarcoma: Challenging Course, Dismal Outcome.
Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution. Most commonly, it occurs as a primary malignancy. In approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated. The clinical presentation varies from a localized solitary mass to severe disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system. Systemic symptoms in terms of weight loss, fever and night sweats often occur. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma.
Introduction
Histiocytic sarcoma is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system [1,2]. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution [1,3,4,5]. Most commonly, it occurs as a primary malignancy; however, in approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated [6]. The clinical presentation varies from a localized solitary mass to a severely disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system [7]. Systemic symptoms in terms of weight loss, fever and night sweats often occur [8]. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics [7]. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months [4]. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma (Figure 1, Figure 2, Figure 3 and Figure 4).
To summarize, this case clearly demonstrates the challenging course of patients with histiocytic sarcoma. The rareness and severe complexity of HS requires a multidisciplinary and specialized approach throughout the diagnostic workout, treatment and follow-up. A rapid establishment of a correct diagnosis, staging of the disease and a personalized, aggressive treatment strategy is essential to improve outcomes in these patients. Even so, the prognosis remains extremely dismal, especially in the case of a disseminated disease at the time of diagnosis.
Author Contributions
K.F.A., L.D.S., P.K. and T.B.P. acquired and interpreted the data. K.F.A., L.D.S., P.K. and T.B.P. drafted the manuscript. K.F.A. and L.D.S. revised the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
The patient gave his written consent for the acquisition and publication of the presented data.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 A 43-year-old previously healthy male was admitted to the surgical unit by his general practitioner with suspicions of acute diverticulitis. The patient complained of constant pain in the epigastric region and under the right and left rib curvature for the previous week upon admission. The pain was intensified when bending forwards and accompanied by an unspecific feeling of fatigue. The patient reported similar symptoms three weeks prior to admission, which remitted spontaneously. Any systemic symptoms of fever, unintended weight loss or night sweats were denied. At admission, the patient had a slight tachycardia; all other vital parameters were normal. Initial laboratory data came out with an elevated C-reactive protein (CRP; 176 mg/L) and a slightly elevated total leukocyte count (9.8 × 109/L). Hepatic and renal biochemical markers were within normal ranges. On physical examination the abdomen was described as tender in the upper quadrants and around the umbilicus but without peritoneal reaction. On suspicion of an intraabdominal abscess, a computed tomography (CT) scan was performed showing free liquid surrounding the liver and the spleen as well as in the small pelvis. There was no free air. However, the upper abdomen was seen with a diffuse reaction in the fatty tissue around the pylorus and ventricle. Radiologically, a perforated ulcer was suspected. The patient underwent a diagnostic laparoscopy, revealing peritonitis in all quadrants and three liters of free fluid. There were no signs of feces, pus or bile. The greater omentum was adherent in a conglomerate consisting of the duodenum, ventricle, pancreas and transverse colon. It was not possible to get a sufficient overview of the structures laparoscopically and the procedure was converted to an explorative laparotomy revealing reactive, stearin-like changes spread in the peritoneal cavity ((A,B), white arrows). The conglomerate was dissected and the posterior part of the ventricle was inspected, revealing no ulcers. The duodenum was mobilized by the Kocher maneuver, also revealing no ulcers or perforation. Perioperatively, an esophago-gastro-duodenoscopy was performed, revealing no ulcerations or pathology. A piece of the omentum was removed for histopathological examination and an intraabdominal drain was placed before ending the procedure. The findings were suspected to be caused by pancreatitis. The postoperative course was uneventful, the drain was removed after seven days and the patient was discharged after eight days with a plan of outpatient follow-up. On postoperative day 17 he was readmitted for drainage of 3.5 L ascites, which had recollected. The pancreas was without signs of pancreatitis on a triple-phase CT. Diagnostic ultrasound described no gallstones.
Figure 2 Histopathology of omental infiltrate and ascitic fluid: (A) Omental fatty tissue with diffuse infiltration of tumor cells (HE×4). (B) The tumor cells were large with vesicular nuclei. Frequent mitoses were seen (HE×40). (C) CD68PGM1 showing characteristic granular cytoplasmic staining (×40). (D) Cytomorphology of the tumor cells in ascitic fluid (×40). A histopathological examination of the resected tissue from the omentum demonstrated a dense and diffuse infiltration of the fatty tissue by large mononuclear cells with large vesicular nuclei with eosinophilic nucleoli. The cytoplasm was eosinophilic with some vacuolization. The cells were of a hematological origin and expressed CD45. They had a fully developed histiocytic differentiation profile with an immunohistochemical expression of CD68, CD163, CD4, CD56 and lysozyme and showed a high proliferative rate that in areas reached 50% (Ki-67). The precursor cell, dendritic cell, melanocytic, neuroendocrine cell, B-cell, T-cell and Langerhans cell markers were negative. No BRAF-mutation could be demonstrated. The PD-L1 was negative. Next generation sequencing (NGS) could not demonstrate any fusions. The NGS panel used was ‘Archers FusionPlex Lymphoma’, investigating the mutation, expression and fusion of 125 genes. Ascitic fluid cytology revealed malignant cells with the same phenotype as the tumor tissue in the omentum. The findings were most compatible with histiocytic sarcoma (HS). A differential diagnosis could be monoblastic leukemia, which was excluded on the examination of bone marrow biopsies. It took 24 days from initial hospitalization until diagnosis, which was confirmed by an expert second opinion. The following day the patient was transferred to a specialized hematological department at a tertiary hospital.
Figure 3 Hybrid imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/CT (2-[18F]FDG PET/CT) was performed for the staging of the disease and as baseline for monitoring of the treatment response. Imaging performed 1 h post-injection of 4.0 MBq/kg 2-[18F]FDG showed a moderately metabolically active, irregular thickening of the peritoneal folds and extensive carcinomatosis-like infiltration in the omentum, mesentery and the pelvic cavity (A–D, yellow arrows). There was minor ascitic fluid in the abdominal and pelvic cavities. There were also metabolically active, enlarged lymph nodes in the mediastinum and upper retroperitoneum. The findings were considered highly suspicious for malignancy. At this point, plasma lactate dehydrogenase (LDH) levels, a future tumor marker in this patient, were elevated (366 U/L; reference range 105–205 U/L). An initial steroid treatment with prednisolone 100 mg/daily had a good effect on the tendency of the recollection of ascites. However, as no standardized treatment for this patient category without comorbidity exists, a hematological specialized tumor board, after consent from the patient, decided to administer a chemotherapy regimen of ifosfamide, carboplatin and etoposide (ICE), which was initiated one month after initial hospitalization. The patient tolerated the treatment well. At clinical follow-up after two cycles of ICE, the patient’s wellbeing was improved, the plasma LDH was normalized and imaging with 2-[18F]FDG PET/CT demonstrated a substantial partial response (PR), both metabolically and morphologically, of the previously described findings in the peritoneum. There were still metabolically active, carcinomatosis-like findings in the omentum, mesentery and on the liver surface (E–H, magenta arrows). There were no pathological lymph nodes. After completion of four cycles of ICE, the metabolic complete response (CR) and a further morphological PR were reported on follow-up 2-[18F]FDG PET/CT (not shown). The plasma LDH was still within a normal range. The patient tolerated the fifth and final cycle of ICE well.
Figure 4 To reduce the risk of HS relapse, an experimental therapeutic approach with high-dose chemotherapy administering a BEAM (carmustine + etoposide + cytarabine + melphalan) regimen and a subsequent autologous stem cell transplant (SCT) was initiated. The patient tolerated the treatment well and at follow-up +60 days after BEAM/SCT the regeneration of bone marrow was considered complete and the tumor marker plasma LDH was still within the reference range (157 U/L). 2-[18F]FDG PET/CT (A) demonstrated a metabolic CR and a further morphological PR. There were now relatively symmetrically localized, metabolically active lymph nodes at the right root of the neck, in both sides of the mediastinum and the lung hilum (black arrow), compatible with possible granulomatous inflammation. Two months later the patient reported a gradual worsening of bone pain in the lumbar and pelvic region. The plasma LDH was now elevated (450 U/L) and thrombocyte and hemoglobin levels were low. A relapse of HS was suspected, which was confirmed by a bone marrow biopsy that showed a massive infiltration of almost 100% of malignant histiocytic cells with blastoid morphology and an immunohistochemical profile similar to previous specimens. Findings on 2-[18F]FDG PET/CT (B) were compatible with a relapse, demonstrating a heterogeneous, pathologically increased FDG-uptake in the bone marrow in the axial and peripheral skeleton (green arrows). There were metabolically active lymph nodes above and now also below the diaphragm. A malignant bone marrow infiltration with a myeloid expansion was considered the cause of the patient’s bone pain. The plasma LDH rose rapidly to 5100 U/L and salvage therapy with an acute myelogenous leukemia regime (CLAG-M; cladribine + cytarabine + mitoxantrone) was initiated. The treatment had a good effect on the patient’s bone pain and wellbeing. The plasma LDH was normalized within days and histopathological examinations showed no tumor cells in the blood and no malignant cells in the bone marrow biopsy. 2-[18F]FDG PET/CT (C) demonstrated a metabolic PR of previously malignant findings in the bone marrow. There were now splenic lesions compatible with abscesses. A second course of CLAG-M was administered and, as the patient had achieved a second CR confirmed by a bone marrow biopsy, a non-myeloablative allogeneic SCT was considered. However, within a short period of time the patient again reported bone pain and he developed cutaneous papules on the trunk end lower extremity from which a biopsy showed HS. The plasma LDH also increased rapidly and 2-[18F]FDG PET/CT (not shown) again demonstrated progression with a pathologically increased FDG-uptake in the bone marrow and new metabolically active cutaneous lesions on the abdomen. The findings were compatible with a systemic relapse and an allogeneic SCT was now not a feasible treatment option. Palliative treatment with a modified FLAG-Ida regime (fludarabine + cytarabine + idarubicin + filgrastim) initially had a good effect on the bone pain; the cutaneous lesions regressed and the plasma LDH decreased. However, the effect was short-lived and the patient experienced intermittent fever, bone pain, fatigue and blood cell counts that demonstrated cytopenia. The plasma LDH again increased. The patient’s clinical condition worsened significantly and after short periods of treatment with high-dose cytarabine and hydroxycarbamide, further treatment attempts with intensive regimen chemotherapy were considered futile. No appropriate protocolled treatment was found suitable for the patient and the treatment aim of long term survival was abated. The patient passed away shortly after, 15 months after his initial hospitalization.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CYTARABINE, FILGRASTIM, FLUDARABINE PHOSPHATE, HYDROXYUREA, IDARUBICIN | DrugsGivenReaction | CC BY | 33671860 | 19,961,558 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic response shortened'. | Histiocytic Sarcoma: Challenging Course, Dismal Outcome.
Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution. Most commonly, it occurs as a primary malignancy. In approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated. The clinical presentation varies from a localized solitary mass to severe disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system. Systemic symptoms in terms of weight loss, fever and night sweats often occur. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma.
Introduction
Histiocytic sarcoma is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system [1,2]. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution [1,3,4,5]. Most commonly, it occurs as a primary malignancy; however, in approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated [6]. The clinical presentation varies from a localized solitary mass to a severely disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system [7]. Systemic symptoms in terms of weight loss, fever and night sweats often occur [8]. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics [7]. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months [4]. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma (Figure 1, Figure 2, Figure 3 and Figure 4).
To summarize, this case clearly demonstrates the challenging course of patients with histiocytic sarcoma. The rareness and severe complexity of HS requires a multidisciplinary and specialized approach throughout the diagnostic workout, treatment and follow-up. A rapid establishment of a correct diagnosis, staging of the disease and a personalized, aggressive treatment strategy is essential to improve outcomes in these patients. Even so, the prognosis remains extremely dismal, especially in the case of a disseminated disease at the time of diagnosis.
Author Contributions
K.F.A., L.D.S., P.K. and T.B.P. acquired and interpreted the data. K.F.A., L.D.S., P.K. and T.B.P. drafted the manuscript. K.F.A. and L.D.S. revised the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
The patient gave his written consent for the acquisition and publication of the presented data.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 A 43-year-old previously healthy male was admitted to the surgical unit by his general practitioner with suspicions of acute diverticulitis. The patient complained of constant pain in the epigastric region and under the right and left rib curvature for the previous week upon admission. The pain was intensified when bending forwards and accompanied by an unspecific feeling of fatigue. The patient reported similar symptoms three weeks prior to admission, which remitted spontaneously. Any systemic symptoms of fever, unintended weight loss or night sweats were denied. At admission, the patient had a slight tachycardia; all other vital parameters were normal. Initial laboratory data came out with an elevated C-reactive protein (CRP; 176 mg/L) and a slightly elevated total leukocyte count (9.8 × 109/L). Hepatic and renal biochemical markers were within normal ranges. On physical examination the abdomen was described as tender in the upper quadrants and around the umbilicus but without peritoneal reaction. On suspicion of an intraabdominal abscess, a computed tomography (CT) scan was performed showing free liquid surrounding the liver and the spleen as well as in the small pelvis. There was no free air. However, the upper abdomen was seen with a diffuse reaction in the fatty tissue around the pylorus and ventricle. Radiologically, a perforated ulcer was suspected. The patient underwent a diagnostic laparoscopy, revealing peritonitis in all quadrants and three liters of free fluid. There were no signs of feces, pus or bile. The greater omentum was adherent in a conglomerate consisting of the duodenum, ventricle, pancreas and transverse colon. It was not possible to get a sufficient overview of the structures laparoscopically and the procedure was converted to an explorative laparotomy revealing reactive, stearin-like changes spread in the peritoneal cavity ((A,B), white arrows). The conglomerate was dissected and the posterior part of the ventricle was inspected, revealing no ulcers. The duodenum was mobilized by the Kocher maneuver, also revealing no ulcers or perforation. Perioperatively, an esophago-gastro-duodenoscopy was performed, revealing no ulcerations or pathology. A piece of the omentum was removed for histopathological examination and an intraabdominal drain was placed before ending the procedure. The findings were suspected to be caused by pancreatitis. The postoperative course was uneventful, the drain was removed after seven days and the patient was discharged after eight days with a plan of outpatient follow-up. On postoperative day 17 he was readmitted for drainage of 3.5 L ascites, which had recollected. The pancreas was without signs of pancreatitis on a triple-phase CT. Diagnostic ultrasound described no gallstones.
Figure 2 Histopathology of omental infiltrate and ascitic fluid: (A) Omental fatty tissue with diffuse infiltration of tumor cells (HE×4). (B) The tumor cells were large with vesicular nuclei. Frequent mitoses were seen (HE×40). (C) CD68PGM1 showing characteristic granular cytoplasmic staining (×40). (D) Cytomorphology of the tumor cells in ascitic fluid (×40). A histopathological examination of the resected tissue from the omentum demonstrated a dense and diffuse infiltration of the fatty tissue by large mononuclear cells with large vesicular nuclei with eosinophilic nucleoli. The cytoplasm was eosinophilic with some vacuolization. The cells were of a hematological origin and expressed CD45. They had a fully developed histiocytic differentiation profile with an immunohistochemical expression of CD68, CD163, CD4, CD56 and lysozyme and showed a high proliferative rate that in areas reached 50% (Ki-67). The precursor cell, dendritic cell, melanocytic, neuroendocrine cell, B-cell, T-cell and Langerhans cell markers were negative. No BRAF-mutation could be demonstrated. The PD-L1 was negative. Next generation sequencing (NGS) could not demonstrate any fusions. The NGS panel used was ‘Archers FusionPlex Lymphoma’, investigating the mutation, expression and fusion of 125 genes. Ascitic fluid cytology revealed malignant cells with the same phenotype as the tumor tissue in the omentum. The findings were most compatible with histiocytic sarcoma (HS). A differential diagnosis could be monoblastic leukemia, which was excluded on the examination of bone marrow biopsies. It took 24 days from initial hospitalization until diagnosis, which was confirmed by an expert second opinion. The following day the patient was transferred to a specialized hematological department at a tertiary hospital.
Figure 3 Hybrid imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/CT (2-[18F]FDG PET/CT) was performed for the staging of the disease and as baseline for monitoring of the treatment response. Imaging performed 1 h post-injection of 4.0 MBq/kg 2-[18F]FDG showed a moderately metabolically active, irregular thickening of the peritoneal folds and extensive carcinomatosis-like infiltration in the omentum, mesentery and the pelvic cavity (A–D, yellow arrows). There was minor ascitic fluid in the abdominal and pelvic cavities. There were also metabolically active, enlarged lymph nodes in the mediastinum and upper retroperitoneum. The findings were considered highly suspicious for malignancy. At this point, plasma lactate dehydrogenase (LDH) levels, a future tumor marker in this patient, were elevated (366 U/L; reference range 105–205 U/L). An initial steroid treatment with prednisolone 100 mg/daily had a good effect on the tendency of the recollection of ascites. However, as no standardized treatment for this patient category without comorbidity exists, a hematological specialized tumor board, after consent from the patient, decided to administer a chemotherapy regimen of ifosfamide, carboplatin and etoposide (ICE), which was initiated one month after initial hospitalization. The patient tolerated the treatment well. At clinical follow-up after two cycles of ICE, the patient’s wellbeing was improved, the plasma LDH was normalized and imaging with 2-[18F]FDG PET/CT demonstrated a substantial partial response (PR), both metabolically and morphologically, of the previously described findings in the peritoneum. There were still metabolically active, carcinomatosis-like findings in the omentum, mesentery and on the liver surface (E–H, magenta arrows). There were no pathological lymph nodes. After completion of four cycles of ICE, the metabolic complete response (CR) and a further morphological PR were reported on follow-up 2-[18F]FDG PET/CT (not shown). The plasma LDH was still within a normal range. The patient tolerated the fifth and final cycle of ICE well.
Figure 4 To reduce the risk of HS relapse, an experimental therapeutic approach with high-dose chemotherapy administering a BEAM (carmustine + etoposide + cytarabine + melphalan) regimen and a subsequent autologous stem cell transplant (SCT) was initiated. The patient tolerated the treatment well and at follow-up +60 days after BEAM/SCT the regeneration of bone marrow was considered complete and the tumor marker plasma LDH was still within the reference range (157 U/L). 2-[18F]FDG PET/CT (A) demonstrated a metabolic CR and a further morphological PR. There were now relatively symmetrically localized, metabolically active lymph nodes at the right root of the neck, in both sides of the mediastinum and the lung hilum (black arrow), compatible with possible granulomatous inflammation. Two months later the patient reported a gradual worsening of bone pain in the lumbar and pelvic region. The plasma LDH was now elevated (450 U/L) and thrombocyte and hemoglobin levels were low. A relapse of HS was suspected, which was confirmed by a bone marrow biopsy that showed a massive infiltration of almost 100% of malignant histiocytic cells with blastoid morphology and an immunohistochemical profile similar to previous specimens. Findings on 2-[18F]FDG PET/CT (B) were compatible with a relapse, demonstrating a heterogeneous, pathologically increased FDG-uptake in the bone marrow in the axial and peripheral skeleton (green arrows). There were metabolically active lymph nodes above and now also below the diaphragm. A malignant bone marrow infiltration with a myeloid expansion was considered the cause of the patient’s bone pain. The plasma LDH rose rapidly to 5100 U/L and salvage therapy with an acute myelogenous leukemia regime (CLAG-M; cladribine + cytarabine + mitoxantrone) was initiated. The treatment had a good effect on the patient’s bone pain and wellbeing. The plasma LDH was normalized within days and histopathological examinations showed no tumor cells in the blood and no malignant cells in the bone marrow biopsy. 2-[18F]FDG PET/CT (C) demonstrated a metabolic PR of previously malignant findings in the bone marrow. There were now splenic lesions compatible with abscesses. A second course of CLAG-M was administered and, as the patient had achieved a second CR confirmed by a bone marrow biopsy, a non-myeloablative allogeneic SCT was considered. However, within a short period of time the patient again reported bone pain and he developed cutaneous papules on the trunk end lower extremity from which a biopsy showed HS. The plasma LDH also increased rapidly and 2-[18F]FDG PET/CT (not shown) again demonstrated progression with a pathologically increased FDG-uptake in the bone marrow and new metabolically active cutaneous lesions on the abdomen. The findings were compatible with a systemic relapse and an allogeneic SCT was now not a feasible treatment option. Palliative treatment with a modified FLAG-Ida regime (fludarabine + cytarabine + idarubicin + filgrastim) initially had a good effect on the bone pain; the cutaneous lesions regressed and the plasma LDH decreased. However, the effect was short-lived and the patient experienced intermittent fever, bone pain, fatigue and blood cell counts that demonstrated cytopenia. The plasma LDH again increased. The patient’s clinical condition worsened significantly and after short periods of treatment with high-dose cytarabine and hydroxycarbamide, further treatment attempts with intensive regimen chemotherapy were considered futile. No appropriate protocolled treatment was found suitable for the patient and the treatment aim of long term survival was abated. The patient passed away shortly after, 15 months after his initial hospitalization.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CYTARABINE, FILGRASTIM, FLUDARABINE PHOSPHATE, HYDROXYUREA, IDARUBICIN | DrugsGivenReaction | CC BY | 33671860 | 19,961,558 | 2021-02-15 |
What was the outcome of reaction 'Condition aggravated'? | Histiocytic Sarcoma: Challenging Course, Dismal Outcome.
Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution. Most commonly, it occurs as a primary malignancy. In approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated. The clinical presentation varies from a localized solitary mass to severe disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system. Systemic symptoms in terms of weight loss, fever and night sweats often occur. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma.
Introduction
Histiocytic sarcoma is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system [1,2]. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution [1,3,4,5]. Most commonly, it occurs as a primary malignancy; however, in approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated [6]. The clinical presentation varies from a localized solitary mass to a severely disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system [7]. Systemic symptoms in terms of weight loss, fever and night sweats often occur [8]. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics [7]. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months [4]. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma (Figure 1, Figure 2, Figure 3 and Figure 4).
To summarize, this case clearly demonstrates the challenging course of patients with histiocytic sarcoma. The rareness and severe complexity of HS requires a multidisciplinary and specialized approach throughout the diagnostic workout, treatment and follow-up. A rapid establishment of a correct diagnosis, staging of the disease and a personalized, aggressive treatment strategy is essential to improve outcomes in these patients. Even so, the prognosis remains extremely dismal, especially in the case of a disseminated disease at the time of diagnosis.
Author Contributions
K.F.A., L.D.S., P.K. and T.B.P. acquired and interpreted the data. K.F.A., L.D.S., P.K. and T.B.P. drafted the manuscript. K.F.A. and L.D.S. revised the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
The patient gave his written consent for the acquisition and publication of the presented data.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 A 43-year-old previously healthy male was admitted to the surgical unit by his general practitioner with suspicions of acute diverticulitis. The patient complained of constant pain in the epigastric region and under the right and left rib curvature for the previous week upon admission. The pain was intensified when bending forwards and accompanied by an unspecific feeling of fatigue. The patient reported similar symptoms three weeks prior to admission, which remitted spontaneously. Any systemic symptoms of fever, unintended weight loss or night sweats were denied. At admission, the patient had a slight tachycardia; all other vital parameters were normal. Initial laboratory data came out with an elevated C-reactive protein (CRP; 176 mg/L) and a slightly elevated total leukocyte count (9.8 × 109/L). Hepatic and renal biochemical markers were within normal ranges. On physical examination the abdomen was described as tender in the upper quadrants and around the umbilicus but without peritoneal reaction. On suspicion of an intraabdominal abscess, a computed tomography (CT) scan was performed showing free liquid surrounding the liver and the spleen as well as in the small pelvis. There was no free air. However, the upper abdomen was seen with a diffuse reaction in the fatty tissue around the pylorus and ventricle. Radiologically, a perforated ulcer was suspected. The patient underwent a diagnostic laparoscopy, revealing peritonitis in all quadrants and three liters of free fluid. There were no signs of feces, pus or bile. The greater omentum was adherent in a conglomerate consisting of the duodenum, ventricle, pancreas and transverse colon. It was not possible to get a sufficient overview of the structures laparoscopically and the procedure was converted to an explorative laparotomy revealing reactive, stearin-like changes spread in the peritoneal cavity ((A,B), white arrows). The conglomerate was dissected and the posterior part of the ventricle was inspected, revealing no ulcers. The duodenum was mobilized by the Kocher maneuver, also revealing no ulcers or perforation. Perioperatively, an esophago-gastro-duodenoscopy was performed, revealing no ulcerations or pathology. A piece of the omentum was removed for histopathological examination and an intraabdominal drain was placed before ending the procedure. The findings were suspected to be caused by pancreatitis. The postoperative course was uneventful, the drain was removed after seven days and the patient was discharged after eight days with a plan of outpatient follow-up. On postoperative day 17 he was readmitted for drainage of 3.5 L ascites, which had recollected. The pancreas was without signs of pancreatitis on a triple-phase CT. Diagnostic ultrasound described no gallstones.
Figure 2 Histopathology of omental infiltrate and ascitic fluid: (A) Omental fatty tissue with diffuse infiltration of tumor cells (HE×4). (B) The tumor cells were large with vesicular nuclei. Frequent mitoses were seen (HE×40). (C) CD68PGM1 showing characteristic granular cytoplasmic staining (×40). (D) Cytomorphology of the tumor cells in ascitic fluid (×40). A histopathological examination of the resected tissue from the omentum demonstrated a dense and diffuse infiltration of the fatty tissue by large mononuclear cells with large vesicular nuclei with eosinophilic nucleoli. The cytoplasm was eosinophilic with some vacuolization. The cells were of a hematological origin and expressed CD45. They had a fully developed histiocytic differentiation profile with an immunohistochemical expression of CD68, CD163, CD4, CD56 and lysozyme and showed a high proliferative rate that in areas reached 50% (Ki-67). The precursor cell, dendritic cell, melanocytic, neuroendocrine cell, B-cell, T-cell and Langerhans cell markers were negative. No BRAF-mutation could be demonstrated. The PD-L1 was negative. Next generation sequencing (NGS) could not demonstrate any fusions. The NGS panel used was ‘Archers FusionPlex Lymphoma’, investigating the mutation, expression and fusion of 125 genes. Ascitic fluid cytology revealed malignant cells with the same phenotype as the tumor tissue in the omentum. The findings were most compatible with histiocytic sarcoma (HS). A differential diagnosis could be monoblastic leukemia, which was excluded on the examination of bone marrow biopsies. It took 24 days from initial hospitalization until diagnosis, which was confirmed by an expert second opinion. The following day the patient was transferred to a specialized hematological department at a tertiary hospital.
Figure 3 Hybrid imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/CT (2-[18F]FDG PET/CT) was performed for the staging of the disease and as baseline for monitoring of the treatment response. Imaging performed 1 h post-injection of 4.0 MBq/kg 2-[18F]FDG showed a moderately metabolically active, irregular thickening of the peritoneal folds and extensive carcinomatosis-like infiltration in the omentum, mesentery and the pelvic cavity (A–D, yellow arrows). There was minor ascitic fluid in the abdominal and pelvic cavities. There were also metabolically active, enlarged lymph nodes in the mediastinum and upper retroperitoneum. The findings were considered highly suspicious for malignancy. At this point, plasma lactate dehydrogenase (LDH) levels, a future tumor marker in this patient, were elevated (366 U/L; reference range 105–205 U/L). An initial steroid treatment with prednisolone 100 mg/daily had a good effect on the tendency of the recollection of ascites. However, as no standardized treatment for this patient category without comorbidity exists, a hematological specialized tumor board, after consent from the patient, decided to administer a chemotherapy regimen of ifosfamide, carboplatin and etoposide (ICE), which was initiated one month after initial hospitalization. The patient tolerated the treatment well. At clinical follow-up after two cycles of ICE, the patient’s wellbeing was improved, the plasma LDH was normalized and imaging with 2-[18F]FDG PET/CT demonstrated a substantial partial response (PR), both metabolically and morphologically, of the previously described findings in the peritoneum. There were still metabolically active, carcinomatosis-like findings in the omentum, mesentery and on the liver surface (E–H, magenta arrows). There were no pathological lymph nodes. After completion of four cycles of ICE, the metabolic complete response (CR) and a further morphological PR were reported on follow-up 2-[18F]FDG PET/CT (not shown). The plasma LDH was still within a normal range. The patient tolerated the fifth and final cycle of ICE well.
Figure 4 To reduce the risk of HS relapse, an experimental therapeutic approach with high-dose chemotherapy administering a BEAM (carmustine + etoposide + cytarabine + melphalan) regimen and a subsequent autologous stem cell transplant (SCT) was initiated. The patient tolerated the treatment well and at follow-up +60 days after BEAM/SCT the regeneration of bone marrow was considered complete and the tumor marker plasma LDH was still within the reference range (157 U/L). 2-[18F]FDG PET/CT (A) demonstrated a metabolic CR and a further morphological PR. There were now relatively symmetrically localized, metabolically active lymph nodes at the right root of the neck, in both sides of the mediastinum and the lung hilum (black arrow), compatible with possible granulomatous inflammation. Two months later the patient reported a gradual worsening of bone pain in the lumbar and pelvic region. The plasma LDH was now elevated (450 U/L) and thrombocyte and hemoglobin levels were low. A relapse of HS was suspected, which was confirmed by a bone marrow biopsy that showed a massive infiltration of almost 100% of malignant histiocytic cells with blastoid morphology and an immunohistochemical profile similar to previous specimens. Findings on 2-[18F]FDG PET/CT (B) were compatible with a relapse, demonstrating a heterogeneous, pathologically increased FDG-uptake in the bone marrow in the axial and peripheral skeleton (green arrows). There were metabolically active lymph nodes above and now also below the diaphragm. A malignant bone marrow infiltration with a myeloid expansion was considered the cause of the patient’s bone pain. The plasma LDH rose rapidly to 5100 U/L and salvage therapy with an acute myelogenous leukemia regime (CLAG-M; cladribine + cytarabine + mitoxantrone) was initiated. The treatment had a good effect on the patient’s bone pain and wellbeing. The plasma LDH was normalized within days and histopathological examinations showed no tumor cells in the blood and no malignant cells in the bone marrow biopsy. 2-[18F]FDG PET/CT (C) demonstrated a metabolic PR of previously malignant findings in the bone marrow. There were now splenic lesions compatible with abscesses. A second course of CLAG-M was administered and, as the patient had achieved a second CR confirmed by a bone marrow biopsy, a non-myeloablative allogeneic SCT was considered. However, within a short period of time the patient again reported bone pain and he developed cutaneous papules on the trunk end lower extremity from which a biopsy showed HS. The plasma LDH also increased rapidly and 2-[18F]FDG PET/CT (not shown) again demonstrated progression with a pathologically increased FDG-uptake in the bone marrow and new metabolically active cutaneous lesions on the abdomen. The findings were compatible with a systemic relapse and an allogeneic SCT was now not a feasible treatment option. Palliative treatment with a modified FLAG-Ida regime (fludarabine + cytarabine + idarubicin + filgrastim) initially had a good effect on the bone pain; the cutaneous lesions regressed and the plasma LDH decreased. However, the effect was short-lived and the patient experienced intermittent fever, bone pain, fatigue and blood cell counts that demonstrated cytopenia. The plasma LDH again increased. The patient’s clinical condition worsened significantly and after short periods of treatment with high-dose cytarabine and hydroxycarbamide, further treatment attempts with intensive regimen chemotherapy were considered futile. No appropriate protocolled treatment was found suitable for the patient and the treatment aim of long term survival was abated. The patient passed away shortly after, 15 months after his initial hospitalization.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Fatal | ReactionOutcome | CC BY | 33671860 | 19,961,558 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atrial thrombosis'. | Percutaneous Occlusion of the Left Atrial Appendage with Thrombus Irresponsive to Antithrombotic Therapy.
We analyzed clinical experience with percutaneous closure of instances of left atrial appendage with thrombus (LAAT) irresponsive to antithrombotic therapy in patients treated in three high-volume cardiology centers. Clinical and procedural data regarding consecutive patients who underwent percutaneous left atrial appendage closure (PLAAC) due to LAAT were retrospectively analyzed. The study population consisted of 17 patients (11 men; 68 ± 14 years; CHA2DS2VASC 4.7 ± 1.9; HASBLED 3 (0-5)) with LAAT confirmed by transesophageal echocardiography, and included 5 patients with mechanical heart valves. Most of the patients (94.1%) received anticoagulation therapy before PLAAC. All LAATs were located in distal portions of the appendage and occupied less than 30% of its volume. Occluding-device implantation was successful in 17 patients; in one, a residual leak was disclosed. Appropriate positioning of occluders required more than 1 attempt in 6 individuals (35.3%); in 3 others (17.6%), the subjects' devices had contact with thrombi. No procedural complications were noted. Midterm follow-up (median: 10 months) revealed no procedure-related complications or clinically diagnosed thromboembolism. Transesophageal echocardiography (TEE) performed after six months revealed device-related thrombus in one patient. We concluded that LAAT irresponsive to antithrombotic therapy might be effectively treated with PLAAC, even in patients with mechanical-valve prostheses.
1. Introduction
Left atrial thrombus formation is disclosed with transesophageal echocardiography in approximately 4% of patients with nonvalvular atrial fibrillation despite receiving appropriate therapy with vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) [1]. It is uncertain which therapeutic action should be undertaken in such a scenario. Standard clinical practice, however (not included in any recommendation), is to intensify anticoagulant therapy [2,3]. Invasive approaches including percutaneous endocardial or epicardial left atrial appendage (LAA) closure, and the surgical excision of LAA might be another alternative to cope with this problem [4,5]. Generally, in patients with nonvalvular atrial fibrillation and a high risk of embolic stroke (CHA2DS2–VASc of at least 2), percutaneous left atrial appendage closure (PLAAC) should be considered in the case of absolute contraindications for long-term oral anticoagulants (OAC) [6]. Additionally, if patients have an elevated bleeding risk score on OAC, refuse to take OAC, or are not compliant to this treatment, PLAAC may be considered as an alternative therapeutic option. Moreover, patients after LAA isolation during catheter ablation or those after stroke on OAC might be candidates for LAA closure [6]. Although LAA thrombus (LAAT) is generally considered a contraindication for any intervention in the left atrium [6], there were percutaneous LAAT closures reported as an ultima ratio treatment option [7,8,9]. Up to now, all published data, which are mostly case reports, cover fewer than 50 patients with percutaneously closed LAAT. The largest series of patients were reported by Tarantini et al. [5], who described 28 patients treated in 8 Italian centers, and by Bordignon et al. [10], who, in 2019, summarized a single-center German experience with 9 patients undergoing percutaneous LAAT closure. As this topic remains elusive and needs more evidence [6], we share the experiences of high-volume Polish centers with percutaneous closure of LAA with a thrombus inside. Additionally, for the first time, we present a subgroup of patients after open-heart surgery with a valve replacement in whom LAAT were jailed with endocardial occluders.
2. Material and Methods
2.1. Study Group
Consecutive patients who underwent percutaneous LAA closure (PLAAC) due to a thrombus in an appendage despite antithrombotic treatment were included in the study. Data were retrospectively collected from three high-volume centers. A decision of left atrium percutaneous closure despite thrombus was taken individually for each patient during heart-team (cardiologists, invasive cardiologists, and cardiac surgeons) meetings according to the routine elaborated in each center. Inclusion criteria to the study were: (1) A decision from the local heart team of PLAAC in the patient with LAAT and (2) subsequent commencement of an invasive procedure with the intention of PLAAC.
In our study population, there were 12 (70.6%) patients with typical indications for left atrial appendage closure (LAAC) according to “EHRA/EPCI expert consensus statement on catheter-based LAAO—an update” [6]. This group included patients with contraindications for long-term oral anticoagulants due to a history of bleeding (8 patients, 47%) and those with ineffective anticoagulation that resulted in stroke (4 patients, 23.5%). The remaining 5 (29.4%) patients had LAAT diagnosed during transesophageal echocardiography (TEE) performed before catheter ablation of left atrial arrhythmias. These patients were treated with anticoagulants prior to the ablation procedure as a standard way of care in patients with atrial arrhythmias.
Patient demography, past medical history, indications for PLAAC, course of procedures, and further follow-up were analyzed. Details regarding preprocedural preparation and technical aspects of PLAAC were examined. The data were directly obtained from physicians who took care of the patients. The diagnostic and therapeutic management of patients was left to the discretion of each center.
2.2. Diagnostic and Therapeutic Procedures
Patients had TEE performed just before and during the PLAAC procedure, in which the thrombus was visualized in multiple views. Thrombus position in LAA was described as located in a proximal or distal portion of LAA. Additionally, the mean percentage of LAA volume covered by thrombus was approximated with a calculation of mean percentage of area covered by LAAT to the LAA area obtained from two TEE projections—30°–60° and 120°–150° (Figure 1). Anatomical characteristics of LAA included: (1) classification to one of four LAA shape variants (chicken wing, windsock, cauliflower and cactus); (2) measurement of the longest (D1) and shortest (D2) diameters of the LAA orifice in the landing-zone position; (3) measurement of LAA depth; and (4) calculation of the orifice eccentricity index (EI) according to an equation: EI = 1 − D2/D1 [11].
Procedural details that were analyzed were: (1) the maximal size of the implanted occluder; (2) mean oversizing of the implanted device, defined as the mean difference between the occluder diameter and orifice diameters (D1 and D2); (3) percentage mean oversizing, defined as the mean oversizing divided by the mean of longest and shortest orifice diameter; (4) the number of occluder positioning attempts; (5) device contact with thrombus during implantation; (6) mobilization of the thrombus into the left atrium; (7) deviation from center’s procedural routine applied in regular non-LAAT patients; (8) duration of TEE and PLAAC procedure (skin to skin). Procedural success, including device and technical success, and complications related to the PLAAC were defined according to the Munich consensus document [12].
2.3. Follow-Up
Follow-up visits were conducted according to the standard of care of each center, which in all cases included clinical evaluation after 6 weeks, 6 months, and 12 months, with TEE performed 6 months after the PLAAC procedure. Information about antiplatelet and/or anticoagulant drug therapy was collected from medical records at four crucial time-points: (1) on hospital admission for PLAAC, (2) during hospital stay before procedure, (3) on discharge, and (4) after 6 months of follow-up.
2.4. Statistical Analyses
Statistical analysis was performed using Statistica software (ver. 13, StatSoft Inc., Tulsa, OK, USA). Continuous variables were tested for normality with the Shapiro–Wilk test and presented as mean ± standard deviation if normally distributed; otherwise, as median and range. Categorical variables are shown as numbers and percentages. The Student’s t- and Wilcoxon–Mann–Whitney tests were applied for between-group comparisons according to data distribution. The chi-squared test and its modification were used to compare categorical data. Values of p < 0.05 were considered statistically significant.
2.5. Ethical Approval
The study was conducted according to Declaration of Helsinki and approved by the bioethical committee of the Medical University of Lodz, Poland (RNN/223/18/KE; 12.06.2018). Each patient gave written and informed consent before having the PLAAC procedure performed.
3. Results
3.1. Study Group’s Clinical Characteristics
Clinical and imaging data (both echocardiographic and fluoroscopic) were complete and of sufficient quality to obtain all required information in all 17 (100%) cases (Table 1 and Table 2). The study group consisted of 17 patients (11 men; 64.7%) aged 34–91 (68.2 ± 13.9) years. All patients suffered from atrial tachyarrhythmias, most commonly atrial fibrillation. The overall risk of thromboembolic events (CHA2DS2VASC score—4.7 ± 1.9) and bleeding episodes (HASBLED score—3 (0–5)) were high.
Six patients had previous cardiothoracic surgery (35.3%). Of those, 5 (29.4%) were valve replacement, including 4 (23.5%) who received mechanical prosthesis, of which 3 (17.6%) were in aortic and 1 (5.9%) in mitral positions. The remaining one patient (5.9%) underwent surgical excision of LAA, but 2 years later, TEE revealed an LAA remnant with a thrombus inside (Supplementary Figure S1). Patients with mechanical-valve prosthesis (MVP) had similar demographic (age: 64.8 ± 3.9 vs. 69.3 ± 15.8, p = 0.4; male sex: 75% vs. 61.5%, p = 0.6) and clinical characteristics (CHA2DS2VASC: 5.0 ± 0.8 vs. 4.6 ± 2.1, p = 0.7; HASBLED: 3.3 ± 1.5 vs. 2.8 ± 1.4, p = 0.6; EF: 43.0 ± 13.9% vs. 44.0 ± 15.5%, p = 0.8) to those of other patients; however, statistical comparison was limited by a small sample size (4 vs. 13 patients). Detailed clinical characteristics of the study group are summarized in Table 1, and detailed data of each patient are shown in Supplementary Table S1.
3.2. Antithrombotic Treatment
Antithrombotic treatment was deemed optimal for all patients. A majority of the study group, 15 patients (88.2%), received oral anticoagulants; 10 (58.8%) of them were on VKA and 5 (29.4%) took DOAC. The 2 (11.8%) remaining individuals were treated atypically. The first was on enoxaparin due to a severe episode of intracerebral hemorrhage on DOAC. The second patient, a 91-year-old woman, received aspirin monotherapy (75 g daily) because all other treatments caused recurrent gastrointestinal bleeding that required blood transfusions. After LAAT diagnosis, the initial antithrombotic therapy was intensified in 12 patients (70.6%), which included the use of high doses of unfractionated heparin intravenously in 1 patient (5.9%), and a combination of anticoagulants (oral or heparins) and antiplatelets (aspirin or/and clopidogrel) in 11 individuals (64.1%). Nevertheless, none of these regimens was fully effective in any patient. However, in all seven patients (41.2%) in whom infusion of unfractionated heparin was administered for at least 7 days, the LAAT had reduced in size; therefore, they had LAAC procedures performed on uninterrupted antithrombotic therapy.
3.3. Echocardiographic Findings
All four anatomical variants of the LAA were revealed in the study group (Table 2). Cauliflower shape was the most common (7 patients; 41.7%). In one individual who had undergone open-chest surgery for LAA elimination due to LAAT despite adequate anticoagulation, a remnant of this anatomical structure was left. As the patient was scheduled for catheter ablation of left atrial arrhythmia, preprocedural TEE was performed and revealed LAAT. The LAA orifices had diameters of 22.5 ± 4.2 mm (longest) and 18.6 ± 2.5 mm (shortest), with an eccentricity index of 0.12 (0.05–0.45), and 34.0 ± 5.5 mm of depth. The thrombi occupied approximately one-fifth of the appendage (22.1 ± 5.6%) and were located in a distal portion of the LAA in all patients.
3.4. Percutaneous Closure of Left Atrial Appendage with Thrombus Procedure
All PLAACs were performed in intravenous conscious sedation, and catheters were inserted through the right femoral vein. Both fluoroscopy and TEE were used for intraprocedural imaging guidance. After trans-septal puncture, the target Activated Clotting Time (ACT) of more than 250 s was obtained in all patients. Maneuvers in the left atrium were performed gently, which meant changing wires in the left pulmonary vein and introducing catheters only to proximal parts of LAA. Auriculography, considered a typical step of PLAAC in all centers, was not performed in 12 (70.5%) patients due to the expected risk of thrombus mobilization, ischemic stroke, and/or systemic thromboembolization. Five patients recruited in one center underwent LAA angiographies with gentle hand contrast injections through pigtail catheters with no clinical signs of stroke or other thromboembolisms.
Technical details of the occluding devices used in PLAAC procedures are summarized in Table 3. Devices were successfully positioned during the first attempt in 11 (64.7%) patients. Three patients (17.6%) had the device repositioned once, and 3 other patients had the device repositioned 3 times. Implanted occluders had diameters 6.3 ± 3.9 mm larger than the LAA orifice, which accounted for 15.2 ± 3.9% of mean percentage oversizing. Eventually, occluders were implanted in appropriate positions in all patients, jailing LAAT and passing stability tests. In one individual, a residual perioccluder leak of a > 5 mm jet was revealed after the device had been deployed, but due to the high eccentricity of the LAA ostium (EI = 0.45), no better position was available. During occluder positioning in 3 patients (17.6%), the devices had direct contact with thrombi (Figure 2, Supplementary Video S2). Nonetheless, in none of these cases was the clot mobilized or were clinical signs of intraprocedural thromboembolic events observed.
No center reported the use of cerebral protection devices; however, during 10 procedures, Sentinel systems (Claret Medical, Santa Rosa, CA, USA) were in operating rooms prepared to be used if needed. All implantations were finished with acute clinical success. No procedure-related or inhospital complications were reported in any of these patients (Table 3).
On discharge, patients most frequently received dual antiplatelet therapy (7 patients; 41.2%); less often, oral anticoagulants with one antiplatelet drug (5 patients; 29.4%); and rarely, triple therapy (3 patients; 17.6%). One of the two remaining patients had warfarin prescribed as monotherapy, and the second was prescribed 75 mg clopidogrel once daily.
3.5. Follow-Up
Median follow-up duration was 10 months (1–18). Eleven patients (64.7%) were observed for at least 6 months after LAAC. There were no midterm-procedure-related complications due to thromboembolic or hemorrhagic events. One patient died due to the progression of heart failure. Five of the 11 patients (45.4%) who had completed the half-year follow-up were on aspirin monotherapy. Three (17.6%) individuals were on a combination of VKA and aspirin, and the remaining two (11.8%) on dual therapy of DOAC with acetylsalicylic acid (ASA). One patient did not receive any anticoagulant or antiplatelet because she had gastrointestinal bleeding that required a blood transfusion while on ASA. Dual therapy with VKA and ASA was upheld in three patients (17.6%) with a history of mechanical-valve implantation. One patient initially treated with Dual antiplatelet therapy (DAPT) had thrombus on the occluder, which dissolved after therapy modification to dabigatran and clopidogrel.
4. Discussion
The main finding of our multicenter analysis is that the percutaneous closure of left atrial appendage thrombi that are irresponsive to standard anticoagulation might be feasible and safe with uneventful midterm follow-up in patients with nonvalvular atrial fibrillation and in those with prior mechanical-valve implantation. Additionally, the intraprocedural direct contact of the clot with an occluder and intraprocedural gentle LAA angiography did not lead to a clinically overt thromboembolic event.
Study groups in two previously published papers regarding the percutaneous closure of LAAT were significantly different, especially in terms of comorbidities and indications for PLAAC. Tarantini et al. [5] presented 28 individuals with nonvalvular atrial fibrillation who had been referred for PLAAC mainly due to major bleeding events on anticoagulants (53%) and so-called “malignant LAA” (29%), which was defined as LAA-persistent thrombus connected to thromboembolic events. On the other hand, Bordignon et al. [10] reported a very specific group of patients consisting of a high percentage (67%) of individuals in whom LAA thrombi were discovered after the electrical isolation of LAA (LAAI), which was performed as a part of an invasive treatment of atrial tachyarrhythmias. Our population that was similar to the one described by Tarantini et al. [5] included several patients with a history of major bleeding events (47%) and individuals in which an LAAT was found accidentally before arrhythmia catheter ablation. More importantly, our population included patients after surgical valve replacement. To the best of our knowledge, only one paper reported a single case of percutaneous LAAT closure in mechanical-valve recipients [13]. This notwithstanding, as thrombi in our patients were located in the LAA and irresponsive to anticoagulation therapy, the percutaneous implantation of LAA occluders was considered to be a unique treatment option. Technically, PLAAC procedures were similar to those in patients without artificial valves, but in individuals with mitral valve prosthesis, special attention was paid to not entrap catheters within mechanical-valve discs and to position occluders with no collision with the valve. Three patients with MVP completed midterm clinical and echocardiographic evaluations, which were uneventful. There is a lack of evidence for PLAAC in patients after MVP implantation because these patients were not included in either LAAC registries or clinical trials [14,15]. Recently, two reports were published and showed favorable results in patients undergoing percutaneous mitral valve procedures and concomitant PLAAC [16,17].
The optimal therapeutic approach for patients with LAAT is still debatable. Some authors argue that the intensification of anticoagulant therapy or changing VKA to DOACs is sufficient [2,3]. Contrastingly, there are examples of devastating failures of such an approach, which subsequently led to abandoning such treatment at one of the high-volume centers [9]. Moreover, due to a high bleeding risk, uptitration of anticoagulants or applying a combination of antiplatelet and anticoagulation therapy is not feasible in many patients, especially from a long-term perspective [18,19,20]. The majority (70%) of our patients had their pharmacotherapy previously modified with no success. Antithrombotic treatment directly prior to PLAAC procedures remains another important issue. Some of our patients had procedures performed on an infusion of unfractionated heparin in order to maintain a small thrombus size and prevent the possible formation of clots on endovascular tools. Unfortunately, neither the Italian nor German groups [5,10] reported this important periprocedural detail. Experience gathered from catheter ablations of atrial fibrillation showed that instrumentation of the left atrium can be relatively safely performed on uninterrupted anticoagulant therapy [21]. Moreover, there is no agreement regarding postprocedural treatment with anticoagulants and/or antiplatelets. Tarantini et al. [5] showed that over one-third (39.3%) of their patients on discharge received dual antiplatelet therapy, which was followed by oral anticoagulants (28%) and low-molecular-weight heparin (18%), while approximately 10% had combinations of antiplatelets and oral anticoagulants prescribed. After 6 months, similarly to the observations of other authors [5,10], approximately half of the patients (45%) in our group were only on aspirin, although many (45%) still remained on oral anticoagulants. There is a general consensus to prescribe aspirin monotherapy for half a year after an LAA closure procedure in typical conditions [6]. The discrepancy in our group was mainly influenced by patients with mechanical prosthesis in whom VKA therapy was mandatory. Two nonvalvular patients had DOAC with clopidogrel initiated, the first because a device-related thrombus had developed on DAPT, and the second due to a left atrial spontaneous echo contrast detected in TEE. Sedaghat et al. [22] reported on relatively frequent (more than 15%) clot formation on LAA occluders. DOAC initiation was documented to successfully resolve device-related thrombi, which was also confirmed in one of our patients.
Technical aspects of the procedure are of high importance mostly due to the considerable threat of intraprocedural thromboembolism. There was no assumption that any particular device was more suitable for percutaneous occlusion of LAA with a thrombus inside. The selection of the device was left to the discretion of the physician performing the procedure. All authors advise performing procedures in a gentle manner with as few maneuvers as possible within LAA [7,8,9,10]. There are suggestions that some of the procedure steps be omitted if possible, i.e., LAA angiography, occluder contact with thrombus, or device repositioning [5,10]. In our study group, LAA angiography was usually omitted, but in a few patients who had had it performed, no thrombus mobilization and no clinical signs of stroke were revealed. There are single reports showing that preimplantation auriculographies were performed [7], although generally, this part of the procedure is thought to be risky [5]. Considering our data and all published by others, there are globally 10 LAAT patients in whom occluders were repositioned during PLAAC, and in none was the thrombus mobilized, nor did stroke occur [5,10]. Direct contact between occluder and LAAT was observed in 17% of patients in our study population. In all of them, occluders were successfully deployed in the first attempt. Some authors advised the use of cerebral protection systems during PLAAC in LAAT patients, although such an approach has not been commonly adopted [5,23]. We are in favor of cerebral protection, especially in patients in whom there is a substantial risk of mobilization of the thrombus (i.e., deep occluder insertion, shallow LAA, or proximal thrombus). These circumstances probably do not happen so frequently because almost all patients reported in the literature had thrombi in distal parts of the LAA [5,10]. Similarly, in our group, LAA clots occupied 30% or less of LAA volume and were located in the distal half of LAA. In the case of larger thrombi, an additional option, successfully applied in 41% of our patients, was to try to reduce its size with extraordinary preprocedural intensive therapy using anticoagulants or antiplatelets. Recently, the use of isoproterenol for emptying echocontrast or sludge prior to LAAC was reported [24,25]. This method could be included in diagnostic and therapeutic approaches in patients with LAAT; however, more data, especially of its safety, are needed.
All authors report favorable data on PLAAC of LAAT from a periprocedural perspective and from midterm follow-ups. Therefore, considering our experience and data from two previous papers [5,10], a multicenter, international, and preferably randomized prospective study should be planned comparing the pharmacological therapy of LAAT irresponsive to optimal anticoagulation to the invasive closure of thrombi inside of LAA.
Important limitations of our analysis are the small sample of the study population and the retrospective data analysis. Additionally, as we did not perform preprocedural and postprocedural cerebral imaging, post-PLAAC silent embolic events cannot be excluded. Due to the retrospective nature of the study, differences in diagnostics and therapy between the centers exist.
5. Conclusions
Left atrial appendage thrombus irresponsive to antithrombotic therapy might be effectively treated with percutaneous closure, including in patients with prior mechanical-valve implantations. Percutaneous left atrial appendage occluders may be safely implanted in LAAT patients even if difficult intraprocedural conditions are met, including direct contact between thrombus and occluding device.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/726/s1. Video S1: left atrial appendage thrombus, Video S2: contact between occluder and left atrial appendage thrombus during device insertion, Figure S1: left atrial appendage remnant with thrombus inside, Table S1: clinical and procedural details of each patient.
Click here for additional data file.
Author Contributions
Conceptualization, K.K.; methodology, K.K., P.J., M.G., Z.K.; software, not applicable; validation, not applicable; formal analysis, I.C., P.P.; investigation, K.K., P.J., W.S., R.P., Z.K., A.B.-S., A.M., M.G.; resources, not applicable; data curation, K.K., I.C.; writing—original-draft preparation, K.K.; writing—review and editing, I.C., R.P., M.G.; visualization, P.J., M.G.; supervision, P.P., Z.K, J.K.W.; project administration, K.K.; funding acquisition, not applicable. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Medical University of Lodz, Poland (RNN/223/18/KE; 12 June 2018).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The majority of the data presented in this study are available in Supplementary Table S1. Further data presented in this study are available on request from the corresponding author.
Conflicts of Interest
Iwona Cygankiewicz, Paweł Ptaszyński, Rafał Płaksej, Anna Babicz-Sadowska, and Agata Markiewicz declare no conflict of interest. The following conflicts of interest are declared: Krzysztof Kaczmarek—proctoring and educational fees from Abbott Co., IL, USA; Witold Streb—proctoring fees from Abbott Co., IL, USA; Piotr Jakubowski—proctoring and educational fees from Abbott Co., IL, USA; Zbigniew Kalarus—proctoring fees from Abbott Co., IL, USA, Marek Grygier—proctoring, research and educational fees from Boston Scientific Co., MA, USA; Advisory Board Member Boston Scientific Co., MA, USA. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Figure 1 Measurement of percentage of left atrial appendage volume occupied by thrombus in transesophageal echocardiography (TEE) (Supplementary Video S1). A1 and A2, Areas 1 and 2; C1 and C2, Circumferences 1 and 2; R, ratio A1/A2.
Figure 2 Occluder in contact with left atrial appendage thrombus.
jcm-10-00726-t001_Table 1Table 1 Clinical characteristics of study population.
Clinical Characteristics
Age, years 68.2 ± 13.9
Sex, male 11 (64.7%)
CHA2DS2VASC 4.7 ± 1.9
CHA2DS2VASC > 3 14 (82.4%)
HASBLED 3 (0–5)
HASBLED > 2 10 (58.8%)
Coronary artery disease 7 (41.2%)
Arterial hypertension 14 (82.4%)
Diabetes 7 (41.2%)
Renal failure 5 (29.4%)
Heart failure
HFrEF
HFmEF 9 (52.9%)
6 (35.3%)
3 (17.6%)
Left ventricular ejection fraction (%) 43.7 ± 14.7
Atrial fibrillation/flutter
Paroxysmal
Persistent
Permanent 17 (100%)
3 (17.6%)
6 (35.3%)
8 (47.1%)
Previous stroke
Ischemic
Hemorrhagic 10 (58.8%)
8 (47.1%)
2 (11.8%)
Previous cardiac surgery
Biological prosthesis
Mechanical prosthesis
LAA excision 6 (35.5%)
1 (5.9%)
4 (23.5%)
1 (5.9%)
Previous implanted pacemaker/ICD device 4 (23.5%)
Anticoagulant or antiplatelet treatment before LAA procedure:
VKA
DOAC
ASA
Enoxaparin 17 (100%)
10 (58.8%)
5 (29.4%)
1 (5.9%)
1 (5.9%)
Antithrombotic therapy intensification before LAA procedure:
Indication for PLAAC
Contraindication for OAC
Stroke on OAC
LAA thrombus on OAC/APT 12 (70.6%)
8 (47.1%)
4 (23.5%)
5 (29.4%)
HFrEF, heart failure with reduced ejection fraction; HF, heart failure with midrange ejection fraction; ICD, implantable cardioverter-defibrillator; VKA, Vitamin K antagonists; DOAC, direct oral anticoagulants; ASA, acetylsalicylic acid; OAC, oral anticoagulant; LAA, left atrial appendage; APT, antiplatelet therapy.
jcm-10-00726-t002_Table 2Table 2 Echocardiographic characteristics of study population.
Echocardiographic Parameters
LAA anatomical type
Cauliflower
Windsock
Chicken wing
Cactus
Undetermined (remnant of LAA)
7 (41.2%)
4 (23.5%)
3 (17.6%)
2 (11.8%)
1 (5.9%)
LAA orifice diameter (mm)
Longest
Shortest
22.5 ± 4.2
18.6 ± 2.5
LAA depth (mm) 34.0 ± 6.3
LAA orifice eccentricity index 0.12 (0.05–0.45)
LAA thrombus location (portion)
½ proximal
½ distal
0 (0.0%)
17 (100%)
Thrombus burden area within LAA/LAA area (%) 22.1 ± 5.6
LAA, left atrial appendage.
jcm-10-00726-t003_Table 3Table 3 Characteristics of percutaneous left atrial appendage closure procedures.
Cardiac rhythm during procedure
Sinus rhythm
Atrial fibrillation/flutter
2 (11.8%)
15 (88.2%)
Anesthesia
Conscious sedation
General anesthesia
17 (100%)
0 (0.0%)
Implanted device
Amplatzer amulet
Watchman
Watchman FLX
13 (76.5%)
2 (11.8%)
2 (11.8%)
Device size (mm) 27 (18–34)
Device mean oversize (mm) 6.3 ± 1.9
Device mean oversize (%) 15.5 ± 3.9
Device deployment attempts
1 attempt
>1 attempt 1 (1–4)
11 (64.7%)
6 (35.3%)
Auriculography 5 (29.4%)
Procedural complication 0 (0.0%)
LAAC success
Device success
Technical success
Procedural success
17 (100%)
16 (94.1%)
16 (94.1%)
TEE duration (min) 46 (20–90)
Skin–skin procedure duration (min) 40 (30–80)
LAAC, left atrial appendage closure; LAA, left atrial appendage; TEE, transesophageal echocardiography. | RIVAROXABAN | DrugsGivenReaction | CC BY | 33673147 | 19,055,045 | 2021-02-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Percutaneous Occlusion of the Left Atrial Appendage with Thrombus Irresponsive to Antithrombotic Therapy.
We analyzed clinical experience with percutaneous closure of instances of left atrial appendage with thrombus (LAAT) irresponsive to antithrombotic therapy in patients treated in three high-volume cardiology centers. Clinical and procedural data regarding consecutive patients who underwent percutaneous left atrial appendage closure (PLAAC) due to LAAT were retrospectively analyzed. The study population consisted of 17 patients (11 men; 68 ± 14 years; CHA2DS2VASC 4.7 ± 1.9; HASBLED 3 (0-5)) with LAAT confirmed by transesophageal echocardiography, and included 5 patients with mechanical heart valves. Most of the patients (94.1%) received anticoagulation therapy before PLAAC. All LAATs were located in distal portions of the appendage and occupied less than 30% of its volume. Occluding-device implantation was successful in 17 patients; in one, a residual leak was disclosed. Appropriate positioning of occluders required more than 1 attempt in 6 individuals (35.3%); in 3 others (17.6%), the subjects' devices had contact with thrombi. No procedural complications were noted. Midterm follow-up (median: 10 months) revealed no procedure-related complications or clinically diagnosed thromboembolism. Transesophageal echocardiography (TEE) performed after six months revealed device-related thrombus in one patient. We concluded that LAAT irresponsive to antithrombotic therapy might be effectively treated with PLAAC, even in patients with mechanical-valve prostheses.
1. Introduction
Left atrial thrombus formation is disclosed with transesophageal echocardiography in approximately 4% of patients with nonvalvular atrial fibrillation despite receiving appropriate therapy with vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) [1]. It is uncertain which therapeutic action should be undertaken in such a scenario. Standard clinical practice, however (not included in any recommendation), is to intensify anticoagulant therapy [2,3]. Invasive approaches including percutaneous endocardial or epicardial left atrial appendage (LAA) closure, and the surgical excision of LAA might be another alternative to cope with this problem [4,5]. Generally, in patients with nonvalvular atrial fibrillation and a high risk of embolic stroke (CHA2DS2–VASc of at least 2), percutaneous left atrial appendage closure (PLAAC) should be considered in the case of absolute contraindications for long-term oral anticoagulants (OAC) [6]. Additionally, if patients have an elevated bleeding risk score on OAC, refuse to take OAC, or are not compliant to this treatment, PLAAC may be considered as an alternative therapeutic option. Moreover, patients after LAA isolation during catheter ablation or those after stroke on OAC might be candidates for LAA closure [6]. Although LAA thrombus (LAAT) is generally considered a contraindication for any intervention in the left atrium [6], there were percutaneous LAAT closures reported as an ultima ratio treatment option [7,8,9]. Up to now, all published data, which are mostly case reports, cover fewer than 50 patients with percutaneously closed LAAT. The largest series of patients were reported by Tarantini et al. [5], who described 28 patients treated in 8 Italian centers, and by Bordignon et al. [10], who, in 2019, summarized a single-center German experience with 9 patients undergoing percutaneous LAAT closure. As this topic remains elusive and needs more evidence [6], we share the experiences of high-volume Polish centers with percutaneous closure of LAA with a thrombus inside. Additionally, for the first time, we present a subgroup of patients after open-heart surgery with a valve replacement in whom LAAT were jailed with endocardial occluders.
2. Material and Methods
2.1. Study Group
Consecutive patients who underwent percutaneous LAA closure (PLAAC) due to a thrombus in an appendage despite antithrombotic treatment were included in the study. Data were retrospectively collected from three high-volume centers. A decision of left atrium percutaneous closure despite thrombus was taken individually for each patient during heart-team (cardiologists, invasive cardiologists, and cardiac surgeons) meetings according to the routine elaborated in each center. Inclusion criteria to the study were: (1) A decision from the local heart team of PLAAC in the patient with LAAT and (2) subsequent commencement of an invasive procedure with the intention of PLAAC.
In our study population, there were 12 (70.6%) patients with typical indications for left atrial appendage closure (LAAC) according to “EHRA/EPCI expert consensus statement on catheter-based LAAO—an update” [6]. This group included patients with contraindications for long-term oral anticoagulants due to a history of bleeding (8 patients, 47%) and those with ineffective anticoagulation that resulted in stroke (4 patients, 23.5%). The remaining 5 (29.4%) patients had LAAT diagnosed during transesophageal echocardiography (TEE) performed before catheter ablation of left atrial arrhythmias. These patients were treated with anticoagulants prior to the ablation procedure as a standard way of care in patients with atrial arrhythmias.
Patient demography, past medical history, indications for PLAAC, course of procedures, and further follow-up were analyzed. Details regarding preprocedural preparation and technical aspects of PLAAC were examined. The data were directly obtained from physicians who took care of the patients. The diagnostic and therapeutic management of patients was left to the discretion of each center.
2.2. Diagnostic and Therapeutic Procedures
Patients had TEE performed just before and during the PLAAC procedure, in which the thrombus was visualized in multiple views. Thrombus position in LAA was described as located in a proximal or distal portion of LAA. Additionally, the mean percentage of LAA volume covered by thrombus was approximated with a calculation of mean percentage of area covered by LAAT to the LAA area obtained from two TEE projections—30°–60° and 120°–150° (Figure 1). Anatomical characteristics of LAA included: (1) classification to one of four LAA shape variants (chicken wing, windsock, cauliflower and cactus); (2) measurement of the longest (D1) and shortest (D2) diameters of the LAA orifice in the landing-zone position; (3) measurement of LAA depth; and (4) calculation of the orifice eccentricity index (EI) according to an equation: EI = 1 − D2/D1 [11].
Procedural details that were analyzed were: (1) the maximal size of the implanted occluder; (2) mean oversizing of the implanted device, defined as the mean difference between the occluder diameter and orifice diameters (D1 and D2); (3) percentage mean oversizing, defined as the mean oversizing divided by the mean of longest and shortest orifice diameter; (4) the number of occluder positioning attempts; (5) device contact with thrombus during implantation; (6) mobilization of the thrombus into the left atrium; (7) deviation from center’s procedural routine applied in regular non-LAAT patients; (8) duration of TEE and PLAAC procedure (skin to skin). Procedural success, including device and technical success, and complications related to the PLAAC were defined according to the Munich consensus document [12].
2.3. Follow-Up
Follow-up visits were conducted according to the standard of care of each center, which in all cases included clinical evaluation after 6 weeks, 6 months, and 12 months, with TEE performed 6 months after the PLAAC procedure. Information about antiplatelet and/or anticoagulant drug therapy was collected from medical records at four crucial time-points: (1) on hospital admission for PLAAC, (2) during hospital stay before procedure, (3) on discharge, and (4) after 6 months of follow-up.
2.4. Statistical Analyses
Statistical analysis was performed using Statistica software (ver. 13, StatSoft Inc., Tulsa, OK, USA). Continuous variables were tested for normality with the Shapiro–Wilk test and presented as mean ± standard deviation if normally distributed; otherwise, as median and range. Categorical variables are shown as numbers and percentages. The Student’s t- and Wilcoxon–Mann–Whitney tests were applied for between-group comparisons according to data distribution. The chi-squared test and its modification were used to compare categorical data. Values of p < 0.05 were considered statistically significant.
2.5. Ethical Approval
The study was conducted according to Declaration of Helsinki and approved by the bioethical committee of the Medical University of Lodz, Poland (RNN/223/18/KE; 12.06.2018). Each patient gave written and informed consent before having the PLAAC procedure performed.
3. Results
3.1. Study Group’s Clinical Characteristics
Clinical and imaging data (both echocardiographic and fluoroscopic) were complete and of sufficient quality to obtain all required information in all 17 (100%) cases (Table 1 and Table 2). The study group consisted of 17 patients (11 men; 64.7%) aged 34–91 (68.2 ± 13.9) years. All patients suffered from atrial tachyarrhythmias, most commonly atrial fibrillation. The overall risk of thromboembolic events (CHA2DS2VASC score—4.7 ± 1.9) and bleeding episodes (HASBLED score—3 (0–5)) were high.
Six patients had previous cardiothoracic surgery (35.3%). Of those, 5 (29.4%) were valve replacement, including 4 (23.5%) who received mechanical prosthesis, of which 3 (17.6%) were in aortic and 1 (5.9%) in mitral positions. The remaining one patient (5.9%) underwent surgical excision of LAA, but 2 years later, TEE revealed an LAA remnant with a thrombus inside (Supplementary Figure S1). Patients with mechanical-valve prosthesis (MVP) had similar demographic (age: 64.8 ± 3.9 vs. 69.3 ± 15.8, p = 0.4; male sex: 75% vs. 61.5%, p = 0.6) and clinical characteristics (CHA2DS2VASC: 5.0 ± 0.8 vs. 4.6 ± 2.1, p = 0.7; HASBLED: 3.3 ± 1.5 vs. 2.8 ± 1.4, p = 0.6; EF: 43.0 ± 13.9% vs. 44.0 ± 15.5%, p = 0.8) to those of other patients; however, statistical comparison was limited by a small sample size (4 vs. 13 patients). Detailed clinical characteristics of the study group are summarized in Table 1, and detailed data of each patient are shown in Supplementary Table S1.
3.2. Antithrombotic Treatment
Antithrombotic treatment was deemed optimal for all patients. A majority of the study group, 15 patients (88.2%), received oral anticoagulants; 10 (58.8%) of them were on VKA and 5 (29.4%) took DOAC. The 2 (11.8%) remaining individuals were treated atypically. The first was on enoxaparin due to a severe episode of intracerebral hemorrhage on DOAC. The second patient, a 91-year-old woman, received aspirin monotherapy (75 g daily) because all other treatments caused recurrent gastrointestinal bleeding that required blood transfusions. After LAAT diagnosis, the initial antithrombotic therapy was intensified in 12 patients (70.6%), which included the use of high doses of unfractionated heparin intravenously in 1 patient (5.9%), and a combination of anticoagulants (oral or heparins) and antiplatelets (aspirin or/and clopidogrel) in 11 individuals (64.1%). Nevertheless, none of these regimens was fully effective in any patient. However, in all seven patients (41.2%) in whom infusion of unfractionated heparin was administered for at least 7 days, the LAAT had reduced in size; therefore, they had LAAC procedures performed on uninterrupted antithrombotic therapy.
3.3. Echocardiographic Findings
All four anatomical variants of the LAA were revealed in the study group (Table 2). Cauliflower shape was the most common (7 patients; 41.7%). In one individual who had undergone open-chest surgery for LAA elimination due to LAAT despite adequate anticoagulation, a remnant of this anatomical structure was left. As the patient was scheduled for catheter ablation of left atrial arrhythmia, preprocedural TEE was performed and revealed LAAT. The LAA orifices had diameters of 22.5 ± 4.2 mm (longest) and 18.6 ± 2.5 mm (shortest), with an eccentricity index of 0.12 (0.05–0.45), and 34.0 ± 5.5 mm of depth. The thrombi occupied approximately one-fifth of the appendage (22.1 ± 5.6%) and were located in a distal portion of the LAA in all patients.
3.4. Percutaneous Closure of Left Atrial Appendage with Thrombus Procedure
All PLAACs were performed in intravenous conscious sedation, and catheters were inserted through the right femoral vein. Both fluoroscopy and TEE were used for intraprocedural imaging guidance. After trans-septal puncture, the target Activated Clotting Time (ACT) of more than 250 s was obtained in all patients. Maneuvers in the left atrium were performed gently, which meant changing wires in the left pulmonary vein and introducing catheters only to proximal parts of LAA. Auriculography, considered a typical step of PLAAC in all centers, was not performed in 12 (70.5%) patients due to the expected risk of thrombus mobilization, ischemic stroke, and/or systemic thromboembolization. Five patients recruited in one center underwent LAA angiographies with gentle hand contrast injections through pigtail catheters with no clinical signs of stroke or other thromboembolisms.
Technical details of the occluding devices used in PLAAC procedures are summarized in Table 3. Devices were successfully positioned during the first attempt in 11 (64.7%) patients. Three patients (17.6%) had the device repositioned once, and 3 other patients had the device repositioned 3 times. Implanted occluders had diameters 6.3 ± 3.9 mm larger than the LAA orifice, which accounted for 15.2 ± 3.9% of mean percentage oversizing. Eventually, occluders were implanted in appropriate positions in all patients, jailing LAAT and passing stability tests. In one individual, a residual perioccluder leak of a > 5 mm jet was revealed after the device had been deployed, but due to the high eccentricity of the LAA ostium (EI = 0.45), no better position was available. During occluder positioning in 3 patients (17.6%), the devices had direct contact with thrombi (Figure 2, Supplementary Video S2). Nonetheless, in none of these cases was the clot mobilized or were clinical signs of intraprocedural thromboembolic events observed.
No center reported the use of cerebral protection devices; however, during 10 procedures, Sentinel systems (Claret Medical, Santa Rosa, CA, USA) were in operating rooms prepared to be used if needed. All implantations were finished with acute clinical success. No procedure-related or inhospital complications were reported in any of these patients (Table 3).
On discharge, patients most frequently received dual antiplatelet therapy (7 patients; 41.2%); less often, oral anticoagulants with one antiplatelet drug (5 patients; 29.4%); and rarely, triple therapy (3 patients; 17.6%). One of the two remaining patients had warfarin prescribed as monotherapy, and the second was prescribed 75 mg clopidogrel once daily.
3.5. Follow-Up
Median follow-up duration was 10 months (1–18). Eleven patients (64.7%) were observed for at least 6 months after LAAC. There were no midterm-procedure-related complications due to thromboembolic or hemorrhagic events. One patient died due to the progression of heart failure. Five of the 11 patients (45.4%) who had completed the half-year follow-up were on aspirin monotherapy. Three (17.6%) individuals were on a combination of VKA and aspirin, and the remaining two (11.8%) on dual therapy of DOAC with acetylsalicylic acid (ASA). One patient did not receive any anticoagulant or antiplatelet because she had gastrointestinal bleeding that required a blood transfusion while on ASA. Dual therapy with VKA and ASA was upheld in three patients (17.6%) with a history of mechanical-valve implantation. One patient initially treated with Dual antiplatelet therapy (DAPT) had thrombus on the occluder, which dissolved after therapy modification to dabigatran and clopidogrel.
4. Discussion
The main finding of our multicenter analysis is that the percutaneous closure of left atrial appendage thrombi that are irresponsive to standard anticoagulation might be feasible and safe with uneventful midterm follow-up in patients with nonvalvular atrial fibrillation and in those with prior mechanical-valve implantation. Additionally, the intraprocedural direct contact of the clot with an occluder and intraprocedural gentle LAA angiography did not lead to a clinically overt thromboembolic event.
Study groups in two previously published papers regarding the percutaneous closure of LAAT were significantly different, especially in terms of comorbidities and indications for PLAAC. Tarantini et al. [5] presented 28 individuals with nonvalvular atrial fibrillation who had been referred for PLAAC mainly due to major bleeding events on anticoagulants (53%) and so-called “malignant LAA” (29%), which was defined as LAA-persistent thrombus connected to thromboembolic events. On the other hand, Bordignon et al. [10] reported a very specific group of patients consisting of a high percentage (67%) of individuals in whom LAA thrombi were discovered after the electrical isolation of LAA (LAAI), which was performed as a part of an invasive treatment of atrial tachyarrhythmias. Our population that was similar to the one described by Tarantini et al. [5] included several patients with a history of major bleeding events (47%) and individuals in which an LAAT was found accidentally before arrhythmia catheter ablation. More importantly, our population included patients after surgical valve replacement. To the best of our knowledge, only one paper reported a single case of percutaneous LAAT closure in mechanical-valve recipients [13]. This notwithstanding, as thrombi in our patients were located in the LAA and irresponsive to anticoagulation therapy, the percutaneous implantation of LAA occluders was considered to be a unique treatment option. Technically, PLAAC procedures were similar to those in patients without artificial valves, but in individuals with mitral valve prosthesis, special attention was paid to not entrap catheters within mechanical-valve discs and to position occluders with no collision with the valve. Three patients with MVP completed midterm clinical and echocardiographic evaluations, which were uneventful. There is a lack of evidence for PLAAC in patients after MVP implantation because these patients were not included in either LAAC registries or clinical trials [14,15]. Recently, two reports were published and showed favorable results in patients undergoing percutaneous mitral valve procedures and concomitant PLAAC [16,17].
The optimal therapeutic approach for patients with LAAT is still debatable. Some authors argue that the intensification of anticoagulant therapy or changing VKA to DOACs is sufficient [2,3]. Contrastingly, there are examples of devastating failures of such an approach, which subsequently led to abandoning such treatment at one of the high-volume centers [9]. Moreover, due to a high bleeding risk, uptitration of anticoagulants or applying a combination of antiplatelet and anticoagulation therapy is not feasible in many patients, especially from a long-term perspective [18,19,20]. The majority (70%) of our patients had their pharmacotherapy previously modified with no success. Antithrombotic treatment directly prior to PLAAC procedures remains another important issue. Some of our patients had procedures performed on an infusion of unfractionated heparin in order to maintain a small thrombus size and prevent the possible formation of clots on endovascular tools. Unfortunately, neither the Italian nor German groups [5,10] reported this important periprocedural detail. Experience gathered from catheter ablations of atrial fibrillation showed that instrumentation of the left atrium can be relatively safely performed on uninterrupted anticoagulant therapy [21]. Moreover, there is no agreement regarding postprocedural treatment with anticoagulants and/or antiplatelets. Tarantini et al. [5] showed that over one-third (39.3%) of their patients on discharge received dual antiplatelet therapy, which was followed by oral anticoagulants (28%) and low-molecular-weight heparin (18%), while approximately 10% had combinations of antiplatelets and oral anticoagulants prescribed. After 6 months, similarly to the observations of other authors [5,10], approximately half of the patients (45%) in our group were only on aspirin, although many (45%) still remained on oral anticoagulants. There is a general consensus to prescribe aspirin monotherapy for half a year after an LAA closure procedure in typical conditions [6]. The discrepancy in our group was mainly influenced by patients with mechanical prosthesis in whom VKA therapy was mandatory. Two nonvalvular patients had DOAC with clopidogrel initiated, the first because a device-related thrombus had developed on DAPT, and the second due to a left atrial spontaneous echo contrast detected in TEE. Sedaghat et al. [22] reported on relatively frequent (more than 15%) clot formation on LAA occluders. DOAC initiation was documented to successfully resolve device-related thrombi, which was also confirmed in one of our patients.
Technical aspects of the procedure are of high importance mostly due to the considerable threat of intraprocedural thromboembolism. There was no assumption that any particular device was more suitable for percutaneous occlusion of LAA with a thrombus inside. The selection of the device was left to the discretion of the physician performing the procedure. All authors advise performing procedures in a gentle manner with as few maneuvers as possible within LAA [7,8,9,10]. There are suggestions that some of the procedure steps be omitted if possible, i.e., LAA angiography, occluder contact with thrombus, or device repositioning [5,10]. In our study group, LAA angiography was usually omitted, but in a few patients who had had it performed, no thrombus mobilization and no clinical signs of stroke were revealed. There are single reports showing that preimplantation auriculographies were performed [7], although generally, this part of the procedure is thought to be risky [5]. Considering our data and all published by others, there are globally 10 LAAT patients in whom occluders were repositioned during PLAAC, and in none was the thrombus mobilized, nor did stroke occur [5,10]. Direct contact between occluder and LAAT was observed in 17% of patients in our study population. In all of them, occluders were successfully deployed in the first attempt. Some authors advised the use of cerebral protection systems during PLAAC in LAAT patients, although such an approach has not been commonly adopted [5,23]. We are in favor of cerebral protection, especially in patients in whom there is a substantial risk of mobilization of the thrombus (i.e., deep occluder insertion, shallow LAA, or proximal thrombus). These circumstances probably do not happen so frequently because almost all patients reported in the literature had thrombi in distal parts of the LAA [5,10]. Similarly, in our group, LAA clots occupied 30% or less of LAA volume and were located in the distal half of LAA. In the case of larger thrombi, an additional option, successfully applied in 41% of our patients, was to try to reduce its size with extraordinary preprocedural intensive therapy using anticoagulants or antiplatelets. Recently, the use of isoproterenol for emptying echocontrast or sludge prior to LAAC was reported [24,25]. This method could be included in diagnostic and therapeutic approaches in patients with LAAT; however, more data, especially of its safety, are needed.
All authors report favorable data on PLAAC of LAAT from a periprocedural perspective and from midterm follow-ups. Therefore, considering our experience and data from two previous papers [5,10], a multicenter, international, and preferably randomized prospective study should be planned comparing the pharmacological therapy of LAAT irresponsive to optimal anticoagulation to the invasive closure of thrombi inside of LAA.
Important limitations of our analysis are the small sample of the study population and the retrospective data analysis. Additionally, as we did not perform preprocedural and postprocedural cerebral imaging, post-PLAAC silent embolic events cannot be excluded. Due to the retrospective nature of the study, differences in diagnostics and therapy between the centers exist.
5. Conclusions
Left atrial appendage thrombus irresponsive to antithrombotic therapy might be effectively treated with percutaneous closure, including in patients with prior mechanical-valve implantations. Percutaneous left atrial appendage occluders may be safely implanted in LAAT patients even if difficult intraprocedural conditions are met, including direct contact between thrombus and occluding device.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/726/s1. Video S1: left atrial appendage thrombus, Video S2: contact between occluder and left atrial appendage thrombus during device insertion, Figure S1: left atrial appendage remnant with thrombus inside, Table S1: clinical and procedural details of each patient.
Click here for additional data file.
Author Contributions
Conceptualization, K.K.; methodology, K.K., P.J., M.G., Z.K.; software, not applicable; validation, not applicable; formal analysis, I.C., P.P.; investigation, K.K., P.J., W.S., R.P., Z.K., A.B.-S., A.M., M.G.; resources, not applicable; data curation, K.K., I.C.; writing—original-draft preparation, K.K.; writing—review and editing, I.C., R.P., M.G.; visualization, P.J., M.G.; supervision, P.P., Z.K, J.K.W.; project administration, K.K.; funding acquisition, not applicable. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Medical University of Lodz, Poland (RNN/223/18/KE; 12 June 2018).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The majority of the data presented in this study are available in Supplementary Table S1. Further data presented in this study are available on request from the corresponding author.
Conflicts of Interest
Iwona Cygankiewicz, Paweł Ptaszyński, Rafał Płaksej, Anna Babicz-Sadowska, and Agata Markiewicz declare no conflict of interest. The following conflicts of interest are declared: Krzysztof Kaczmarek—proctoring and educational fees from Abbott Co., IL, USA; Witold Streb—proctoring fees from Abbott Co., IL, USA; Piotr Jakubowski—proctoring and educational fees from Abbott Co., IL, USA; Zbigniew Kalarus—proctoring fees from Abbott Co., IL, USA, Marek Grygier—proctoring, research and educational fees from Boston Scientific Co., MA, USA; Advisory Board Member Boston Scientific Co., MA, USA. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Figure 1 Measurement of percentage of left atrial appendage volume occupied by thrombus in transesophageal echocardiography (TEE) (Supplementary Video S1). A1 and A2, Areas 1 and 2; C1 and C2, Circumferences 1 and 2; R, ratio A1/A2.
Figure 2 Occluder in contact with left atrial appendage thrombus.
jcm-10-00726-t001_Table 1Table 1 Clinical characteristics of study population.
Clinical Characteristics
Age, years 68.2 ± 13.9
Sex, male 11 (64.7%)
CHA2DS2VASC 4.7 ± 1.9
CHA2DS2VASC > 3 14 (82.4%)
HASBLED 3 (0–5)
HASBLED > 2 10 (58.8%)
Coronary artery disease 7 (41.2%)
Arterial hypertension 14 (82.4%)
Diabetes 7 (41.2%)
Renal failure 5 (29.4%)
Heart failure
HFrEF
HFmEF 9 (52.9%)
6 (35.3%)
3 (17.6%)
Left ventricular ejection fraction (%) 43.7 ± 14.7
Atrial fibrillation/flutter
Paroxysmal
Persistent
Permanent 17 (100%)
3 (17.6%)
6 (35.3%)
8 (47.1%)
Previous stroke
Ischemic
Hemorrhagic 10 (58.8%)
8 (47.1%)
2 (11.8%)
Previous cardiac surgery
Biological prosthesis
Mechanical prosthesis
LAA excision 6 (35.5%)
1 (5.9%)
4 (23.5%)
1 (5.9%)
Previous implanted pacemaker/ICD device 4 (23.5%)
Anticoagulant or antiplatelet treatment before LAA procedure:
VKA
DOAC
ASA
Enoxaparin 17 (100%)
10 (58.8%)
5 (29.4%)
1 (5.9%)
1 (5.9%)
Antithrombotic therapy intensification before LAA procedure:
Indication for PLAAC
Contraindication for OAC
Stroke on OAC
LAA thrombus on OAC/APT 12 (70.6%)
8 (47.1%)
4 (23.5%)
5 (29.4%)
HFrEF, heart failure with reduced ejection fraction; HF, heart failure with midrange ejection fraction; ICD, implantable cardioverter-defibrillator; VKA, Vitamin K antagonists; DOAC, direct oral anticoagulants; ASA, acetylsalicylic acid; OAC, oral anticoagulant; LAA, left atrial appendage; APT, antiplatelet therapy.
jcm-10-00726-t002_Table 2Table 2 Echocardiographic characteristics of study population.
Echocardiographic Parameters
LAA anatomical type
Cauliflower
Windsock
Chicken wing
Cactus
Undetermined (remnant of LAA)
7 (41.2%)
4 (23.5%)
3 (17.6%)
2 (11.8%)
1 (5.9%)
LAA orifice diameter (mm)
Longest
Shortest
22.5 ± 4.2
18.6 ± 2.5
LAA depth (mm) 34.0 ± 6.3
LAA orifice eccentricity index 0.12 (0.05–0.45)
LAA thrombus location (portion)
½ proximal
½ distal
0 (0.0%)
17 (100%)
Thrombus burden area within LAA/LAA area (%) 22.1 ± 5.6
LAA, left atrial appendage.
jcm-10-00726-t003_Table 3Table 3 Characteristics of percutaneous left atrial appendage closure procedures.
Cardiac rhythm during procedure
Sinus rhythm
Atrial fibrillation/flutter
2 (11.8%)
15 (88.2%)
Anesthesia
Conscious sedation
General anesthesia
17 (100%)
0 (0.0%)
Implanted device
Amplatzer amulet
Watchman
Watchman FLX
13 (76.5%)
2 (11.8%)
2 (11.8%)
Device size (mm) 27 (18–34)
Device mean oversize (mm) 6.3 ± 1.9
Device mean oversize (%) 15.5 ± 3.9
Device deployment attempts
1 attempt
>1 attempt 1 (1–4)
11 (64.7%)
6 (35.3%)
Auriculography 5 (29.4%)
Procedural complication 0 (0.0%)
LAAC success
Device success
Technical success
Procedural success
17 (100%)
16 (94.1%)
16 (94.1%)
TEE duration (min) 46 (20–90)
Skin–skin procedure duration (min) 40 (30–80)
LAAC, left atrial appendage closure; LAA, left atrial appendage; TEE, transesophageal echocardiography. | RIVAROXABAN | DrugsGivenReaction | CC BY | 33673147 | 19,055,045 | 2021-02-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal haemorrhage'. | Percutaneous Occlusion of the Left Atrial Appendage with Thrombus Irresponsive to Antithrombotic Therapy.
We analyzed clinical experience with percutaneous closure of instances of left atrial appendage with thrombus (LAAT) irresponsive to antithrombotic therapy in patients treated in three high-volume cardiology centers. Clinical and procedural data regarding consecutive patients who underwent percutaneous left atrial appendage closure (PLAAC) due to LAAT were retrospectively analyzed. The study population consisted of 17 patients (11 men; 68 ± 14 years; CHA2DS2VASC 4.7 ± 1.9; HASBLED 3 (0-5)) with LAAT confirmed by transesophageal echocardiography, and included 5 patients with mechanical heart valves. Most of the patients (94.1%) received anticoagulation therapy before PLAAC. All LAATs were located in distal portions of the appendage and occupied less than 30% of its volume. Occluding-device implantation was successful in 17 patients; in one, a residual leak was disclosed. Appropriate positioning of occluders required more than 1 attempt in 6 individuals (35.3%); in 3 others (17.6%), the subjects' devices had contact with thrombi. No procedural complications were noted. Midterm follow-up (median: 10 months) revealed no procedure-related complications or clinically diagnosed thromboembolism. Transesophageal echocardiography (TEE) performed after six months revealed device-related thrombus in one patient. We concluded that LAAT irresponsive to antithrombotic therapy might be effectively treated with PLAAC, even in patients with mechanical-valve prostheses.
1. Introduction
Left atrial thrombus formation is disclosed with transesophageal echocardiography in approximately 4% of patients with nonvalvular atrial fibrillation despite receiving appropriate therapy with vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) [1]. It is uncertain which therapeutic action should be undertaken in such a scenario. Standard clinical practice, however (not included in any recommendation), is to intensify anticoagulant therapy [2,3]. Invasive approaches including percutaneous endocardial or epicardial left atrial appendage (LAA) closure, and the surgical excision of LAA might be another alternative to cope with this problem [4,5]. Generally, in patients with nonvalvular atrial fibrillation and a high risk of embolic stroke (CHA2DS2–VASc of at least 2), percutaneous left atrial appendage closure (PLAAC) should be considered in the case of absolute contraindications for long-term oral anticoagulants (OAC) [6]. Additionally, if patients have an elevated bleeding risk score on OAC, refuse to take OAC, or are not compliant to this treatment, PLAAC may be considered as an alternative therapeutic option. Moreover, patients after LAA isolation during catheter ablation or those after stroke on OAC might be candidates for LAA closure [6]. Although LAA thrombus (LAAT) is generally considered a contraindication for any intervention in the left atrium [6], there were percutaneous LAAT closures reported as an ultima ratio treatment option [7,8,9]. Up to now, all published data, which are mostly case reports, cover fewer than 50 patients with percutaneously closed LAAT. The largest series of patients were reported by Tarantini et al. [5], who described 28 patients treated in 8 Italian centers, and by Bordignon et al. [10], who, in 2019, summarized a single-center German experience with 9 patients undergoing percutaneous LAAT closure. As this topic remains elusive and needs more evidence [6], we share the experiences of high-volume Polish centers with percutaneous closure of LAA with a thrombus inside. Additionally, for the first time, we present a subgroup of patients after open-heart surgery with a valve replacement in whom LAAT were jailed with endocardial occluders.
2. Material and Methods
2.1. Study Group
Consecutive patients who underwent percutaneous LAA closure (PLAAC) due to a thrombus in an appendage despite antithrombotic treatment were included in the study. Data were retrospectively collected from three high-volume centers. A decision of left atrium percutaneous closure despite thrombus was taken individually for each patient during heart-team (cardiologists, invasive cardiologists, and cardiac surgeons) meetings according to the routine elaborated in each center. Inclusion criteria to the study were: (1) A decision from the local heart team of PLAAC in the patient with LAAT and (2) subsequent commencement of an invasive procedure with the intention of PLAAC.
In our study population, there were 12 (70.6%) patients with typical indications for left atrial appendage closure (LAAC) according to “EHRA/EPCI expert consensus statement on catheter-based LAAO—an update” [6]. This group included patients with contraindications for long-term oral anticoagulants due to a history of bleeding (8 patients, 47%) and those with ineffective anticoagulation that resulted in stroke (4 patients, 23.5%). The remaining 5 (29.4%) patients had LAAT diagnosed during transesophageal echocardiography (TEE) performed before catheter ablation of left atrial arrhythmias. These patients were treated with anticoagulants prior to the ablation procedure as a standard way of care in patients with atrial arrhythmias.
Patient demography, past medical history, indications for PLAAC, course of procedures, and further follow-up were analyzed. Details regarding preprocedural preparation and technical aspects of PLAAC were examined. The data were directly obtained from physicians who took care of the patients. The diagnostic and therapeutic management of patients was left to the discretion of each center.
2.2. Diagnostic and Therapeutic Procedures
Patients had TEE performed just before and during the PLAAC procedure, in which the thrombus was visualized in multiple views. Thrombus position in LAA was described as located in a proximal or distal portion of LAA. Additionally, the mean percentage of LAA volume covered by thrombus was approximated with a calculation of mean percentage of area covered by LAAT to the LAA area obtained from two TEE projections—30°–60° and 120°–150° (Figure 1). Anatomical characteristics of LAA included: (1) classification to one of four LAA shape variants (chicken wing, windsock, cauliflower and cactus); (2) measurement of the longest (D1) and shortest (D2) diameters of the LAA orifice in the landing-zone position; (3) measurement of LAA depth; and (4) calculation of the orifice eccentricity index (EI) according to an equation: EI = 1 − D2/D1 [11].
Procedural details that were analyzed were: (1) the maximal size of the implanted occluder; (2) mean oversizing of the implanted device, defined as the mean difference between the occluder diameter and orifice diameters (D1 and D2); (3) percentage mean oversizing, defined as the mean oversizing divided by the mean of longest and shortest orifice diameter; (4) the number of occluder positioning attempts; (5) device contact with thrombus during implantation; (6) mobilization of the thrombus into the left atrium; (7) deviation from center’s procedural routine applied in regular non-LAAT patients; (8) duration of TEE and PLAAC procedure (skin to skin). Procedural success, including device and technical success, and complications related to the PLAAC were defined according to the Munich consensus document [12].
2.3. Follow-Up
Follow-up visits were conducted according to the standard of care of each center, which in all cases included clinical evaluation after 6 weeks, 6 months, and 12 months, with TEE performed 6 months after the PLAAC procedure. Information about antiplatelet and/or anticoagulant drug therapy was collected from medical records at four crucial time-points: (1) on hospital admission for PLAAC, (2) during hospital stay before procedure, (3) on discharge, and (4) after 6 months of follow-up.
2.4. Statistical Analyses
Statistical analysis was performed using Statistica software (ver. 13, StatSoft Inc., Tulsa, OK, USA). Continuous variables were tested for normality with the Shapiro–Wilk test and presented as mean ± standard deviation if normally distributed; otherwise, as median and range. Categorical variables are shown as numbers and percentages. The Student’s t- and Wilcoxon–Mann–Whitney tests were applied for between-group comparisons according to data distribution. The chi-squared test and its modification were used to compare categorical data. Values of p < 0.05 were considered statistically significant.
2.5. Ethical Approval
The study was conducted according to Declaration of Helsinki and approved by the bioethical committee of the Medical University of Lodz, Poland (RNN/223/18/KE; 12.06.2018). Each patient gave written and informed consent before having the PLAAC procedure performed.
3. Results
3.1. Study Group’s Clinical Characteristics
Clinical and imaging data (both echocardiographic and fluoroscopic) were complete and of sufficient quality to obtain all required information in all 17 (100%) cases (Table 1 and Table 2). The study group consisted of 17 patients (11 men; 64.7%) aged 34–91 (68.2 ± 13.9) years. All patients suffered from atrial tachyarrhythmias, most commonly atrial fibrillation. The overall risk of thromboembolic events (CHA2DS2VASC score—4.7 ± 1.9) and bleeding episodes (HASBLED score—3 (0–5)) were high.
Six patients had previous cardiothoracic surgery (35.3%). Of those, 5 (29.4%) were valve replacement, including 4 (23.5%) who received mechanical prosthesis, of which 3 (17.6%) were in aortic and 1 (5.9%) in mitral positions. The remaining one patient (5.9%) underwent surgical excision of LAA, but 2 years later, TEE revealed an LAA remnant with a thrombus inside (Supplementary Figure S1). Patients with mechanical-valve prosthesis (MVP) had similar demographic (age: 64.8 ± 3.9 vs. 69.3 ± 15.8, p = 0.4; male sex: 75% vs. 61.5%, p = 0.6) and clinical characteristics (CHA2DS2VASC: 5.0 ± 0.8 vs. 4.6 ± 2.1, p = 0.7; HASBLED: 3.3 ± 1.5 vs. 2.8 ± 1.4, p = 0.6; EF: 43.0 ± 13.9% vs. 44.0 ± 15.5%, p = 0.8) to those of other patients; however, statistical comparison was limited by a small sample size (4 vs. 13 patients). Detailed clinical characteristics of the study group are summarized in Table 1, and detailed data of each patient are shown in Supplementary Table S1.
3.2. Antithrombotic Treatment
Antithrombotic treatment was deemed optimal for all patients. A majority of the study group, 15 patients (88.2%), received oral anticoagulants; 10 (58.8%) of them were on VKA and 5 (29.4%) took DOAC. The 2 (11.8%) remaining individuals were treated atypically. The first was on enoxaparin due to a severe episode of intracerebral hemorrhage on DOAC. The second patient, a 91-year-old woman, received aspirin monotherapy (75 g daily) because all other treatments caused recurrent gastrointestinal bleeding that required blood transfusions. After LAAT diagnosis, the initial antithrombotic therapy was intensified in 12 patients (70.6%), which included the use of high doses of unfractionated heparin intravenously in 1 patient (5.9%), and a combination of anticoagulants (oral or heparins) and antiplatelets (aspirin or/and clopidogrel) in 11 individuals (64.1%). Nevertheless, none of these regimens was fully effective in any patient. However, in all seven patients (41.2%) in whom infusion of unfractionated heparin was administered for at least 7 days, the LAAT had reduced in size; therefore, they had LAAC procedures performed on uninterrupted antithrombotic therapy.
3.3. Echocardiographic Findings
All four anatomical variants of the LAA were revealed in the study group (Table 2). Cauliflower shape was the most common (7 patients; 41.7%). In one individual who had undergone open-chest surgery for LAA elimination due to LAAT despite adequate anticoagulation, a remnant of this anatomical structure was left. As the patient was scheduled for catheter ablation of left atrial arrhythmia, preprocedural TEE was performed and revealed LAAT. The LAA orifices had diameters of 22.5 ± 4.2 mm (longest) and 18.6 ± 2.5 mm (shortest), with an eccentricity index of 0.12 (0.05–0.45), and 34.0 ± 5.5 mm of depth. The thrombi occupied approximately one-fifth of the appendage (22.1 ± 5.6%) and were located in a distal portion of the LAA in all patients.
3.4. Percutaneous Closure of Left Atrial Appendage with Thrombus Procedure
All PLAACs were performed in intravenous conscious sedation, and catheters were inserted through the right femoral vein. Both fluoroscopy and TEE were used for intraprocedural imaging guidance. After trans-septal puncture, the target Activated Clotting Time (ACT) of more than 250 s was obtained in all patients. Maneuvers in the left atrium were performed gently, which meant changing wires in the left pulmonary vein and introducing catheters only to proximal parts of LAA. Auriculography, considered a typical step of PLAAC in all centers, was not performed in 12 (70.5%) patients due to the expected risk of thrombus mobilization, ischemic stroke, and/or systemic thromboembolization. Five patients recruited in one center underwent LAA angiographies with gentle hand contrast injections through pigtail catheters with no clinical signs of stroke or other thromboembolisms.
Technical details of the occluding devices used in PLAAC procedures are summarized in Table 3. Devices were successfully positioned during the first attempt in 11 (64.7%) patients. Three patients (17.6%) had the device repositioned once, and 3 other patients had the device repositioned 3 times. Implanted occluders had diameters 6.3 ± 3.9 mm larger than the LAA orifice, which accounted for 15.2 ± 3.9% of mean percentage oversizing. Eventually, occluders were implanted in appropriate positions in all patients, jailing LAAT and passing stability tests. In one individual, a residual perioccluder leak of a > 5 mm jet was revealed after the device had been deployed, but due to the high eccentricity of the LAA ostium (EI = 0.45), no better position was available. During occluder positioning in 3 patients (17.6%), the devices had direct contact with thrombi (Figure 2, Supplementary Video S2). Nonetheless, in none of these cases was the clot mobilized or were clinical signs of intraprocedural thromboembolic events observed.
No center reported the use of cerebral protection devices; however, during 10 procedures, Sentinel systems (Claret Medical, Santa Rosa, CA, USA) were in operating rooms prepared to be used if needed. All implantations were finished with acute clinical success. No procedure-related or inhospital complications were reported in any of these patients (Table 3).
On discharge, patients most frequently received dual antiplatelet therapy (7 patients; 41.2%); less often, oral anticoagulants with one antiplatelet drug (5 patients; 29.4%); and rarely, triple therapy (3 patients; 17.6%). One of the two remaining patients had warfarin prescribed as monotherapy, and the second was prescribed 75 mg clopidogrel once daily.
3.5. Follow-Up
Median follow-up duration was 10 months (1–18). Eleven patients (64.7%) were observed for at least 6 months after LAAC. There were no midterm-procedure-related complications due to thromboembolic or hemorrhagic events. One patient died due to the progression of heart failure. Five of the 11 patients (45.4%) who had completed the half-year follow-up were on aspirin monotherapy. Three (17.6%) individuals were on a combination of VKA and aspirin, and the remaining two (11.8%) on dual therapy of DOAC with acetylsalicylic acid (ASA). One patient did not receive any anticoagulant or antiplatelet because she had gastrointestinal bleeding that required a blood transfusion while on ASA. Dual therapy with VKA and ASA was upheld in three patients (17.6%) with a history of mechanical-valve implantation. One patient initially treated with Dual antiplatelet therapy (DAPT) had thrombus on the occluder, which dissolved after therapy modification to dabigatran and clopidogrel.
4. Discussion
The main finding of our multicenter analysis is that the percutaneous closure of left atrial appendage thrombi that are irresponsive to standard anticoagulation might be feasible and safe with uneventful midterm follow-up in patients with nonvalvular atrial fibrillation and in those with prior mechanical-valve implantation. Additionally, the intraprocedural direct contact of the clot with an occluder and intraprocedural gentle LAA angiography did not lead to a clinically overt thromboembolic event.
Study groups in two previously published papers regarding the percutaneous closure of LAAT were significantly different, especially in terms of comorbidities and indications for PLAAC. Tarantini et al. [5] presented 28 individuals with nonvalvular atrial fibrillation who had been referred for PLAAC mainly due to major bleeding events on anticoagulants (53%) and so-called “malignant LAA” (29%), which was defined as LAA-persistent thrombus connected to thromboembolic events. On the other hand, Bordignon et al. [10] reported a very specific group of patients consisting of a high percentage (67%) of individuals in whom LAA thrombi were discovered after the electrical isolation of LAA (LAAI), which was performed as a part of an invasive treatment of atrial tachyarrhythmias. Our population that was similar to the one described by Tarantini et al. [5] included several patients with a history of major bleeding events (47%) and individuals in which an LAAT was found accidentally before arrhythmia catheter ablation. More importantly, our population included patients after surgical valve replacement. To the best of our knowledge, only one paper reported a single case of percutaneous LAAT closure in mechanical-valve recipients [13]. This notwithstanding, as thrombi in our patients were located in the LAA and irresponsive to anticoagulation therapy, the percutaneous implantation of LAA occluders was considered to be a unique treatment option. Technically, PLAAC procedures were similar to those in patients without artificial valves, but in individuals with mitral valve prosthesis, special attention was paid to not entrap catheters within mechanical-valve discs and to position occluders with no collision with the valve. Three patients with MVP completed midterm clinical and echocardiographic evaluations, which were uneventful. There is a lack of evidence for PLAAC in patients after MVP implantation because these patients were not included in either LAAC registries or clinical trials [14,15]. Recently, two reports were published and showed favorable results in patients undergoing percutaneous mitral valve procedures and concomitant PLAAC [16,17].
The optimal therapeutic approach for patients with LAAT is still debatable. Some authors argue that the intensification of anticoagulant therapy or changing VKA to DOACs is sufficient [2,3]. Contrastingly, there are examples of devastating failures of such an approach, which subsequently led to abandoning such treatment at one of the high-volume centers [9]. Moreover, due to a high bleeding risk, uptitration of anticoagulants or applying a combination of antiplatelet and anticoagulation therapy is not feasible in many patients, especially from a long-term perspective [18,19,20]. The majority (70%) of our patients had their pharmacotherapy previously modified with no success. Antithrombotic treatment directly prior to PLAAC procedures remains another important issue. Some of our patients had procedures performed on an infusion of unfractionated heparin in order to maintain a small thrombus size and prevent the possible formation of clots on endovascular tools. Unfortunately, neither the Italian nor German groups [5,10] reported this important periprocedural detail. Experience gathered from catheter ablations of atrial fibrillation showed that instrumentation of the left atrium can be relatively safely performed on uninterrupted anticoagulant therapy [21]. Moreover, there is no agreement regarding postprocedural treatment with anticoagulants and/or antiplatelets. Tarantini et al. [5] showed that over one-third (39.3%) of their patients on discharge received dual antiplatelet therapy, which was followed by oral anticoagulants (28%) and low-molecular-weight heparin (18%), while approximately 10% had combinations of antiplatelets and oral anticoagulants prescribed. After 6 months, similarly to the observations of other authors [5,10], approximately half of the patients (45%) in our group were only on aspirin, although many (45%) still remained on oral anticoagulants. There is a general consensus to prescribe aspirin monotherapy for half a year after an LAA closure procedure in typical conditions [6]. The discrepancy in our group was mainly influenced by patients with mechanical prosthesis in whom VKA therapy was mandatory. Two nonvalvular patients had DOAC with clopidogrel initiated, the first because a device-related thrombus had developed on DAPT, and the second due to a left atrial spontaneous echo contrast detected in TEE. Sedaghat et al. [22] reported on relatively frequent (more than 15%) clot formation on LAA occluders. DOAC initiation was documented to successfully resolve device-related thrombi, which was also confirmed in one of our patients.
Technical aspects of the procedure are of high importance mostly due to the considerable threat of intraprocedural thromboembolism. There was no assumption that any particular device was more suitable for percutaneous occlusion of LAA with a thrombus inside. The selection of the device was left to the discretion of the physician performing the procedure. All authors advise performing procedures in a gentle manner with as few maneuvers as possible within LAA [7,8,9,10]. There are suggestions that some of the procedure steps be omitted if possible, i.e., LAA angiography, occluder contact with thrombus, or device repositioning [5,10]. In our study group, LAA angiography was usually omitted, but in a few patients who had had it performed, no thrombus mobilization and no clinical signs of stroke were revealed. There are single reports showing that preimplantation auriculographies were performed [7], although generally, this part of the procedure is thought to be risky [5]. Considering our data and all published by others, there are globally 10 LAAT patients in whom occluders were repositioned during PLAAC, and in none was the thrombus mobilized, nor did stroke occur [5,10]. Direct contact between occluder and LAAT was observed in 17% of patients in our study population. In all of them, occluders were successfully deployed in the first attempt. Some authors advised the use of cerebral protection systems during PLAAC in LAAT patients, although such an approach has not been commonly adopted [5,23]. We are in favor of cerebral protection, especially in patients in whom there is a substantial risk of mobilization of the thrombus (i.e., deep occluder insertion, shallow LAA, or proximal thrombus). These circumstances probably do not happen so frequently because almost all patients reported in the literature had thrombi in distal parts of the LAA [5,10]. Similarly, in our group, LAA clots occupied 30% or less of LAA volume and were located in the distal half of LAA. In the case of larger thrombi, an additional option, successfully applied in 41% of our patients, was to try to reduce its size with extraordinary preprocedural intensive therapy using anticoagulants or antiplatelets. Recently, the use of isoproterenol for emptying echocontrast or sludge prior to LAAC was reported [24,25]. This method could be included in diagnostic and therapeutic approaches in patients with LAAT; however, more data, especially of its safety, are needed.
All authors report favorable data on PLAAC of LAAT from a periprocedural perspective and from midterm follow-ups. Therefore, considering our experience and data from two previous papers [5,10], a multicenter, international, and preferably randomized prospective study should be planned comparing the pharmacological therapy of LAAT irresponsive to optimal anticoagulation to the invasive closure of thrombi inside of LAA.
Important limitations of our analysis are the small sample of the study population and the retrospective data analysis. Additionally, as we did not perform preprocedural and postprocedural cerebral imaging, post-PLAAC silent embolic events cannot be excluded. Due to the retrospective nature of the study, differences in diagnostics and therapy between the centers exist.
5. Conclusions
Left atrial appendage thrombus irresponsive to antithrombotic therapy might be effectively treated with percutaneous closure, including in patients with prior mechanical-valve implantations. Percutaneous left atrial appendage occluders may be safely implanted in LAAT patients even if difficult intraprocedural conditions are met, including direct contact between thrombus and occluding device.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/726/s1. Video S1: left atrial appendage thrombus, Video S2: contact between occluder and left atrial appendage thrombus during device insertion, Figure S1: left atrial appendage remnant with thrombus inside, Table S1: clinical and procedural details of each patient.
Click here for additional data file.
Author Contributions
Conceptualization, K.K.; methodology, K.K., P.J., M.G., Z.K.; software, not applicable; validation, not applicable; formal analysis, I.C., P.P.; investigation, K.K., P.J., W.S., R.P., Z.K., A.B.-S., A.M., M.G.; resources, not applicable; data curation, K.K., I.C.; writing—original-draft preparation, K.K.; writing—review and editing, I.C., R.P., M.G.; visualization, P.J., M.G.; supervision, P.P., Z.K, J.K.W.; project administration, K.K.; funding acquisition, not applicable. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Medical University of Lodz, Poland (RNN/223/18/KE; 12 June 2018).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The majority of the data presented in this study are available in Supplementary Table S1. Further data presented in this study are available on request from the corresponding author.
Conflicts of Interest
Iwona Cygankiewicz, Paweł Ptaszyński, Rafał Płaksej, Anna Babicz-Sadowska, and Agata Markiewicz declare no conflict of interest. The following conflicts of interest are declared: Krzysztof Kaczmarek—proctoring and educational fees from Abbott Co., IL, USA; Witold Streb—proctoring fees from Abbott Co., IL, USA; Piotr Jakubowski—proctoring and educational fees from Abbott Co., IL, USA; Zbigniew Kalarus—proctoring fees from Abbott Co., IL, USA, Marek Grygier—proctoring, research and educational fees from Boston Scientific Co., MA, USA; Advisory Board Member Boston Scientific Co., MA, USA. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Figure 1 Measurement of percentage of left atrial appendage volume occupied by thrombus in transesophageal echocardiography (TEE) (Supplementary Video S1). A1 and A2, Areas 1 and 2; C1 and C2, Circumferences 1 and 2; R, ratio A1/A2.
Figure 2 Occluder in contact with left atrial appendage thrombus.
jcm-10-00726-t001_Table 1Table 1 Clinical characteristics of study population.
Clinical Characteristics
Age, years 68.2 ± 13.9
Sex, male 11 (64.7%)
CHA2DS2VASC 4.7 ± 1.9
CHA2DS2VASC > 3 14 (82.4%)
HASBLED 3 (0–5)
HASBLED > 2 10 (58.8%)
Coronary artery disease 7 (41.2%)
Arterial hypertension 14 (82.4%)
Diabetes 7 (41.2%)
Renal failure 5 (29.4%)
Heart failure
HFrEF
HFmEF 9 (52.9%)
6 (35.3%)
3 (17.6%)
Left ventricular ejection fraction (%) 43.7 ± 14.7
Atrial fibrillation/flutter
Paroxysmal
Persistent
Permanent 17 (100%)
3 (17.6%)
6 (35.3%)
8 (47.1%)
Previous stroke
Ischemic
Hemorrhagic 10 (58.8%)
8 (47.1%)
2 (11.8%)
Previous cardiac surgery
Biological prosthesis
Mechanical prosthesis
LAA excision 6 (35.5%)
1 (5.9%)
4 (23.5%)
1 (5.9%)
Previous implanted pacemaker/ICD device 4 (23.5%)
Anticoagulant or antiplatelet treatment before LAA procedure:
VKA
DOAC
ASA
Enoxaparin 17 (100%)
10 (58.8%)
5 (29.4%)
1 (5.9%)
1 (5.9%)
Antithrombotic therapy intensification before LAA procedure:
Indication for PLAAC
Contraindication for OAC
Stroke on OAC
LAA thrombus on OAC/APT 12 (70.6%)
8 (47.1%)
4 (23.5%)
5 (29.4%)
HFrEF, heart failure with reduced ejection fraction; HF, heart failure with midrange ejection fraction; ICD, implantable cardioverter-defibrillator; VKA, Vitamin K antagonists; DOAC, direct oral anticoagulants; ASA, acetylsalicylic acid; OAC, oral anticoagulant; LAA, left atrial appendage; APT, antiplatelet therapy.
jcm-10-00726-t002_Table 2Table 2 Echocardiographic characteristics of study population.
Echocardiographic Parameters
LAA anatomical type
Cauliflower
Windsock
Chicken wing
Cactus
Undetermined (remnant of LAA)
7 (41.2%)
4 (23.5%)
3 (17.6%)
2 (11.8%)
1 (5.9%)
LAA orifice diameter (mm)
Longest
Shortest
22.5 ± 4.2
18.6 ± 2.5
LAA depth (mm) 34.0 ± 6.3
LAA orifice eccentricity index 0.12 (0.05–0.45)
LAA thrombus location (portion)
½ proximal
½ distal
0 (0.0%)
17 (100%)
Thrombus burden area within LAA/LAA area (%) 22.1 ± 5.6
LAA, left atrial appendage.
jcm-10-00726-t003_Table 3Table 3 Characteristics of percutaneous left atrial appendage closure procedures.
Cardiac rhythm during procedure
Sinus rhythm
Atrial fibrillation/flutter
2 (11.8%)
15 (88.2%)
Anesthesia
Conscious sedation
General anesthesia
17 (100%)
0 (0.0%)
Implanted device
Amplatzer amulet
Watchman
Watchman FLX
13 (76.5%)
2 (11.8%)
2 (11.8%)
Device size (mm) 27 (18–34)
Device mean oversize (mm) 6.3 ± 1.9
Device mean oversize (%) 15.5 ± 3.9
Device deployment attempts
1 attempt
>1 attempt 1 (1–4)
11 (64.7%)
6 (35.3%)
Auriculography 5 (29.4%)
Procedural complication 0 (0.0%)
LAAC success
Device success
Technical success
Procedural success
17 (100%)
16 (94.1%)
16 (94.1%)
TEE duration (min) 46 (20–90)
Skin–skin procedure duration (min) 40 (30–80)
LAAC, left atrial appendage closure; LAA, left atrial appendage; TEE, transesophageal echocardiography. | RIVAROXABAN | DrugsGivenReaction | CC BY | 33673147 | 19,055,045 | 2021-02-12 |
What was the administration route of drug 'RIVAROXABAN'? | Percutaneous Occlusion of the Left Atrial Appendage with Thrombus Irresponsive to Antithrombotic Therapy.
We analyzed clinical experience with percutaneous closure of instances of left atrial appendage with thrombus (LAAT) irresponsive to antithrombotic therapy in patients treated in three high-volume cardiology centers. Clinical and procedural data regarding consecutive patients who underwent percutaneous left atrial appendage closure (PLAAC) due to LAAT were retrospectively analyzed. The study population consisted of 17 patients (11 men; 68 ± 14 years; CHA2DS2VASC 4.7 ± 1.9; HASBLED 3 (0-5)) with LAAT confirmed by transesophageal echocardiography, and included 5 patients with mechanical heart valves. Most of the patients (94.1%) received anticoagulation therapy before PLAAC. All LAATs were located in distal portions of the appendage and occupied less than 30% of its volume. Occluding-device implantation was successful in 17 patients; in one, a residual leak was disclosed. Appropriate positioning of occluders required more than 1 attempt in 6 individuals (35.3%); in 3 others (17.6%), the subjects' devices had contact with thrombi. No procedural complications were noted. Midterm follow-up (median: 10 months) revealed no procedure-related complications or clinically diagnosed thromboembolism. Transesophageal echocardiography (TEE) performed after six months revealed device-related thrombus in one patient. We concluded that LAAT irresponsive to antithrombotic therapy might be effectively treated with PLAAC, even in patients with mechanical-valve prostheses.
1. Introduction
Left atrial thrombus formation is disclosed with transesophageal echocardiography in approximately 4% of patients with nonvalvular atrial fibrillation despite receiving appropriate therapy with vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) [1]. It is uncertain which therapeutic action should be undertaken in such a scenario. Standard clinical practice, however (not included in any recommendation), is to intensify anticoagulant therapy [2,3]. Invasive approaches including percutaneous endocardial or epicardial left atrial appendage (LAA) closure, and the surgical excision of LAA might be another alternative to cope with this problem [4,5]. Generally, in patients with nonvalvular atrial fibrillation and a high risk of embolic stroke (CHA2DS2–VASc of at least 2), percutaneous left atrial appendage closure (PLAAC) should be considered in the case of absolute contraindications for long-term oral anticoagulants (OAC) [6]. Additionally, if patients have an elevated bleeding risk score on OAC, refuse to take OAC, or are not compliant to this treatment, PLAAC may be considered as an alternative therapeutic option. Moreover, patients after LAA isolation during catheter ablation or those after stroke on OAC might be candidates for LAA closure [6]. Although LAA thrombus (LAAT) is generally considered a contraindication for any intervention in the left atrium [6], there were percutaneous LAAT closures reported as an ultima ratio treatment option [7,8,9]. Up to now, all published data, which are mostly case reports, cover fewer than 50 patients with percutaneously closed LAAT. The largest series of patients were reported by Tarantini et al. [5], who described 28 patients treated in 8 Italian centers, and by Bordignon et al. [10], who, in 2019, summarized a single-center German experience with 9 patients undergoing percutaneous LAAT closure. As this topic remains elusive and needs more evidence [6], we share the experiences of high-volume Polish centers with percutaneous closure of LAA with a thrombus inside. Additionally, for the first time, we present a subgroup of patients after open-heart surgery with a valve replacement in whom LAAT were jailed with endocardial occluders.
2. Material and Methods
2.1. Study Group
Consecutive patients who underwent percutaneous LAA closure (PLAAC) due to a thrombus in an appendage despite antithrombotic treatment were included in the study. Data were retrospectively collected from three high-volume centers. A decision of left atrium percutaneous closure despite thrombus was taken individually for each patient during heart-team (cardiologists, invasive cardiologists, and cardiac surgeons) meetings according to the routine elaborated in each center. Inclusion criteria to the study were: (1) A decision from the local heart team of PLAAC in the patient with LAAT and (2) subsequent commencement of an invasive procedure with the intention of PLAAC.
In our study population, there were 12 (70.6%) patients with typical indications for left atrial appendage closure (LAAC) according to “EHRA/EPCI expert consensus statement on catheter-based LAAO—an update” [6]. This group included patients with contraindications for long-term oral anticoagulants due to a history of bleeding (8 patients, 47%) and those with ineffective anticoagulation that resulted in stroke (4 patients, 23.5%). The remaining 5 (29.4%) patients had LAAT diagnosed during transesophageal echocardiography (TEE) performed before catheter ablation of left atrial arrhythmias. These patients were treated with anticoagulants prior to the ablation procedure as a standard way of care in patients with atrial arrhythmias.
Patient demography, past medical history, indications for PLAAC, course of procedures, and further follow-up were analyzed. Details regarding preprocedural preparation and technical aspects of PLAAC were examined. The data were directly obtained from physicians who took care of the patients. The diagnostic and therapeutic management of patients was left to the discretion of each center.
2.2. Diagnostic and Therapeutic Procedures
Patients had TEE performed just before and during the PLAAC procedure, in which the thrombus was visualized in multiple views. Thrombus position in LAA was described as located in a proximal or distal portion of LAA. Additionally, the mean percentage of LAA volume covered by thrombus was approximated with a calculation of mean percentage of area covered by LAAT to the LAA area obtained from two TEE projections—30°–60° and 120°–150° (Figure 1). Anatomical characteristics of LAA included: (1) classification to one of four LAA shape variants (chicken wing, windsock, cauliflower and cactus); (2) measurement of the longest (D1) and shortest (D2) diameters of the LAA orifice in the landing-zone position; (3) measurement of LAA depth; and (4) calculation of the orifice eccentricity index (EI) according to an equation: EI = 1 − D2/D1 [11].
Procedural details that were analyzed were: (1) the maximal size of the implanted occluder; (2) mean oversizing of the implanted device, defined as the mean difference between the occluder diameter and orifice diameters (D1 and D2); (3) percentage mean oversizing, defined as the mean oversizing divided by the mean of longest and shortest orifice diameter; (4) the number of occluder positioning attempts; (5) device contact with thrombus during implantation; (6) mobilization of the thrombus into the left atrium; (7) deviation from center’s procedural routine applied in regular non-LAAT patients; (8) duration of TEE and PLAAC procedure (skin to skin). Procedural success, including device and technical success, and complications related to the PLAAC were defined according to the Munich consensus document [12].
2.3. Follow-Up
Follow-up visits were conducted according to the standard of care of each center, which in all cases included clinical evaluation after 6 weeks, 6 months, and 12 months, with TEE performed 6 months after the PLAAC procedure. Information about antiplatelet and/or anticoagulant drug therapy was collected from medical records at four crucial time-points: (1) on hospital admission for PLAAC, (2) during hospital stay before procedure, (3) on discharge, and (4) after 6 months of follow-up.
2.4. Statistical Analyses
Statistical analysis was performed using Statistica software (ver. 13, StatSoft Inc., Tulsa, OK, USA). Continuous variables were tested for normality with the Shapiro–Wilk test and presented as mean ± standard deviation if normally distributed; otherwise, as median and range. Categorical variables are shown as numbers and percentages. The Student’s t- and Wilcoxon–Mann–Whitney tests were applied for between-group comparisons according to data distribution. The chi-squared test and its modification were used to compare categorical data. Values of p < 0.05 were considered statistically significant.
2.5. Ethical Approval
The study was conducted according to Declaration of Helsinki and approved by the bioethical committee of the Medical University of Lodz, Poland (RNN/223/18/KE; 12.06.2018). Each patient gave written and informed consent before having the PLAAC procedure performed.
3. Results
3.1. Study Group’s Clinical Characteristics
Clinical and imaging data (both echocardiographic and fluoroscopic) were complete and of sufficient quality to obtain all required information in all 17 (100%) cases (Table 1 and Table 2). The study group consisted of 17 patients (11 men; 64.7%) aged 34–91 (68.2 ± 13.9) years. All patients suffered from atrial tachyarrhythmias, most commonly atrial fibrillation. The overall risk of thromboembolic events (CHA2DS2VASC score—4.7 ± 1.9) and bleeding episodes (HASBLED score—3 (0–5)) were high.
Six patients had previous cardiothoracic surgery (35.3%). Of those, 5 (29.4%) were valve replacement, including 4 (23.5%) who received mechanical prosthesis, of which 3 (17.6%) were in aortic and 1 (5.9%) in mitral positions. The remaining one patient (5.9%) underwent surgical excision of LAA, but 2 years later, TEE revealed an LAA remnant with a thrombus inside (Supplementary Figure S1). Patients with mechanical-valve prosthesis (MVP) had similar demographic (age: 64.8 ± 3.9 vs. 69.3 ± 15.8, p = 0.4; male sex: 75% vs. 61.5%, p = 0.6) and clinical characteristics (CHA2DS2VASC: 5.0 ± 0.8 vs. 4.6 ± 2.1, p = 0.7; HASBLED: 3.3 ± 1.5 vs. 2.8 ± 1.4, p = 0.6; EF: 43.0 ± 13.9% vs. 44.0 ± 15.5%, p = 0.8) to those of other patients; however, statistical comparison was limited by a small sample size (4 vs. 13 patients). Detailed clinical characteristics of the study group are summarized in Table 1, and detailed data of each patient are shown in Supplementary Table S1.
3.2. Antithrombotic Treatment
Antithrombotic treatment was deemed optimal for all patients. A majority of the study group, 15 patients (88.2%), received oral anticoagulants; 10 (58.8%) of them were on VKA and 5 (29.4%) took DOAC. The 2 (11.8%) remaining individuals were treated atypically. The first was on enoxaparin due to a severe episode of intracerebral hemorrhage on DOAC. The second patient, a 91-year-old woman, received aspirin monotherapy (75 g daily) because all other treatments caused recurrent gastrointestinal bleeding that required blood transfusions. After LAAT diagnosis, the initial antithrombotic therapy was intensified in 12 patients (70.6%), which included the use of high doses of unfractionated heparin intravenously in 1 patient (5.9%), and a combination of anticoagulants (oral or heparins) and antiplatelets (aspirin or/and clopidogrel) in 11 individuals (64.1%). Nevertheless, none of these regimens was fully effective in any patient. However, in all seven patients (41.2%) in whom infusion of unfractionated heparin was administered for at least 7 days, the LAAT had reduced in size; therefore, they had LAAC procedures performed on uninterrupted antithrombotic therapy.
3.3. Echocardiographic Findings
All four anatomical variants of the LAA were revealed in the study group (Table 2). Cauliflower shape was the most common (7 patients; 41.7%). In one individual who had undergone open-chest surgery for LAA elimination due to LAAT despite adequate anticoagulation, a remnant of this anatomical structure was left. As the patient was scheduled for catheter ablation of left atrial arrhythmia, preprocedural TEE was performed and revealed LAAT. The LAA orifices had diameters of 22.5 ± 4.2 mm (longest) and 18.6 ± 2.5 mm (shortest), with an eccentricity index of 0.12 (0.05–0.45), and 34.0 ± 5.5 mm of depth. The thrombi occupied approximately one-fifth of the appendage (22.1 ± 5.6%) and were located in a distal portion of the LAA in all patients.
3.4. Percutaneous Closure of Left Atrial Appendage with Thrombus Procedure
All PLAACs were performed in intravenous conscious sedation, and catheters were inserted through the right femoral vein. Both fluoroscopy and TEE were used for intraprocedural imaging guidance. After trans-septal puncture, the target Activated Clotting Time (ACT) of more than 250 s was obtained in all patients. Maneuvers in the left atrium were performed gently, which meant changing wires in the left pulmonary vein and introducing catheters only to proximal parts of LAA. Auriculography, considered a typical step of PLAAC in all centers, was not performed in 12 (70.5%) patients due to the expected risk of thrombus mobilization, ischemic stroke, and/or systemic thromboembolization. Five patients recruited in one center underwent LAA angiographies with gentle hand contrast injections through pigtail catheters with no clinical signs of stroke or other thromboembolisms.
Technical details of the occluding devices used in PLAAC procedures are summarized in Table 3. Devices were successfully positioned during the first attempt in 11 (64.7%) patients. Three patients (17.6%) had the device repositioned once, and 3 other patients had the device repositioned 3 times. Implanted occluders had diameters 6.3 ± 3.9 mm larger than the LAA orifice, which accounted for 15.2 ± 3.9% of mean percentage oversizing. Eventually, occluders were implanted in appropriate positions in all patients, jailing LAAT and passing stability tests. In one individual, a residual perioccluder leak of a > 5 mm jet was revealed after the device had been deployed, but due to the high eccentricity of the LAA ostium (EI = 0.45), no better position was available. During occluder positioning in 3 patients (17.6%), the devices had direct contact with thrombi (Figure 2, Supplementary Video S2). Nonetheless, in none of these cases was the clot mobilized or were clinical signs of intraprocedural thromboembolic events observed.
No center reported the use of cerebral protection devices; however, during 10 procedures, Sentinel systems (Claret Medical, Santa Rosa, CA, USA) were in operating rooms prepared to be used if needed. All implantations were finished with acute clinical success. No procedure-related or inhospital complications were reported in any of these patients (Table 3).
On discharge, patients most frequently received dual antiplatelet therapy (7 patients; 41.2%); less often, oral anticoagulants with one antiplatelet drug (5 patients; 29.4%); and rarely, triple therapy (3 patients; 17.6%). One of the two remaining patients had warfarin prescribed as monotherapy, and the second was prescribed 75 mg clopidogrel once daily.
3.5. Follow-Up
Median follow-up duration was 10 months (1–18). Eleven patients (64.7%) were observed for at least 6 months after LAAC. There were no midterm-procedure-related complications due to thromboembolic or hemorrhagic events. One patient died due to the progression of heart failure. Five of the 11 patients (45.4%) who had completed the half-year follow-up were on aspirin monotherapy. Three (17.6%) individuals were on a combination of VKA and aspirin, and the remaining two (11.8%) on dual therapy of DOAC with acetylsalicylic acid (ASA). One patient did not receive any anticoagulant or antiplatelet because she had gastrointestinal bleeding that required a blood transfusion while on ASA. Dual therapy with VKA and ASA was upheld in three patients (17.6%) with a history of mechanical-valve implantation. One patient initially treated with Dual antiplatelet therapy (DAPT) had thrombus on the occluder, which dissolved after therapy modification to dabigatran and clopidogrel.
4. Discussion
The main finding of our multicenter analysis is that the percutaneous closure of left atrial appendage thrombi that are irresponsive to standard anticoagulation might be feasible and safe with uneventful midterm follow-up in patients with nonvalvular atrial fibrillation and in those with prior mechanical-valve implantation. Additionally, the intraprocedural direct contact of the clot with an occluder and intraprocedural gentle LAA angiography did not lead to a clinically overt thromboembolic event.
Study groups in two previously published papers regarding the percutaneous closure of LAAT were significantly different, especially in terms of comorbidities and indications for PLAAC. Tarantini et al. [5] presented 28 individuals with nonvalvular atrial fibrillation who had been referred for PLAAC mainly due to major bleeding events on anticoagulants (53%) and so-called “malignant LAA” (29%), which was defined as LAA-persistent thrombus connected to thromboembolic events. On the other hand, Bordignon et al. [10] reported a very specific group of patients consisting of a high percentage (67%) of individuals in whom LAA thrombi were discovered after the electrical isolation of LAA (LAAI), which was performed as a part of an invasive treatment of atrial tachyarrhythmias. Our population that was similar to the one described by Tarantini et al. [5] included several patients with a history of major bleeding events (47%) and individuals in which an LAAT was found accidentally before arrhythmia catheter ablation. More importantly, our population included patients after surgical valve replacement. To the best of our knowledge, only one paper reported a single case of percutaneous LAAT closure in mechanical-valve recipients [13]. This notwithstanding, as thrombi in our patients were located in the LAA and irresponsive to anticoagulation therapy, the percutaneous implantation of LAA occluders was considered to be a unique treatment option. Technically, PLAAC procedures were similar to those in patients without artificial valves, but in individuals with mitral valve prosthesis, special attention was paid to not entrap catheters within mechanical-valve discs and to position occluders with no collision with the valve. Three patients with MVP completed midterm clinical and echocardiographic evaluations, which were uneventful. There is a lack of evidence for PLAAC in patients after MVP implantation because these patients were not included in either LAAC registries or clinical trials [14,15]. Recently, two reports were published and showed favorable results in patients undergoing percutaneous mitral valve procedures and concomitant PLAAC [16,17].
The optimal therapeutic approach for patients with LAAT is still debatable. Some authors argue that the intensification of anticoagulant therapy or changing VKA to DOACs is sufficient [2,3]. Contrastingly, there are examples of devastating failures of such an approach, which subsequently led to abandoning such treatment at one of the high-volume centers [9]. Moreover, due to a high bleeding risk, uptitration of anticoagulants or applying a combination of antiplatelet and anticoagulation therapy is not feasible in many patients, especially from a long-term perspective [18,19,20]. The majority (70%) of our patients had their pharmacotherapy previously modified with no success. Antithrombotic treatment directly prior to PLAAC procedures remains another important issue. Some of our patients had procedures performed on an infusion of unfractionated heparin in order to maintain a small thrombus size and prevent the possible formation of clots on endovascular tools. Unfortunately, neither the Italian nor German groups [5,10] reported this important periprocedural detail. Experience gathered from catheter ablations of atrial fibrillation showed that instrumentation of the left atrium can be relatively safely performed on uninterrupted anticoagulant therapy [21]. Moreover, there is no agreement regarding postprocedural treatment with anticoagulants and/or antiplatelets. Tarantini et al. [5] showed that over one-third (39.3%) of their patients on discharge received dual antiplatelet therapy, which was followed by oral anticoagulants (28%) and low-molecular-weight heparin (18%), while approximately 10% had combinations of antiplatelets and oral anticoagulants prescribed. After 6 months, similarly to the observations of other authors [5,10], approximately half of the patients (45%) in our group were only on aspirin, although many (45%) still remained on oral anticoagulants. There is a general consensus to prescribe aspirin monotherapy for half a year after an LAA closure procedure in typical conditions [6]. The discrepancy in our group was mainly influenced by patients with mechanical prosthesis in whom VKA therapy was mandatory. Two nonvalvular patients had DOAC with clopidogrel initiated, the first because a device-related thrombus had developed on DAPT, and the second due to a left atrial spontaneous echo contrast detected in TEE. Sedaghat et al. [22] reported on relatively frequent (more than 15%) clot formation on LAA occluders. DOAC initiation was documented to successfully resolve device-related thrombi, which was also confirmed in one of our patients.
Technical aspects of the procedure are of high importance mostly due to the considerable threat of intraprocedural thromboembolism. There was no assumption that any particular device was more suitable for percutaneous occlusion of LAA with a thrombus inside. The selection of the device was left to the discretion of the physician performing the procedure. All authors advise performing procedures in a gentle manner with as few maneuvers as possible within LAA [7,8,9,10]. There are suggestions that some of the procedure steps be omitted if possible, i.e., LAA angiography, occluder contact with thrombus, or device repositioning [5,10]. In our study group, LAA angiography was usually omitted, but in a few patients who had had it performed, no thrombus mobilization and no clinical signs of stroke were revealed. There are single reports showing that preimplantation auriculographies were performed [7], although generally, this part of the procedure is thought to be risky [5]. Considering our data and all published by others, there are globally 10 LAAT patients in whom occluders were repositioned during PLAAC, and in none was the thrombus mobilized, nor did stroke occur [5,10]. Direct contact between occluder and LAAT was observed in 17% of patients in our study population. In all of them, occluders were successfully deployed in the first attempt. Some authors advised the use of cerebral protection systems during PLAAC in LAAT patients, although such an approach has not been commonly adopted [5,23]. We are in favor of cerebral protection, especially in patients in whom there is a substantial risk of mobilization of the thrombus (i.e., deep occluder insertion, shallow LAA, or proximal thrombus). These circumstances probably do not happen so frequently because almost all patients reported in the literature had thrombi in distal parts of the LAA [5,10]. Similarly, in our group, LAA clots occupied 30% or less of LAA volume and were located in the distal half of LAA. In the case of larger thrombi, an additional option, successfully applied in 41% of our patients, was to try to reduce its size with extraordinary preprocedural intensive therapy using anticoagulants or antiplatelets. Recently, the use of isoproterenol for emptying echocontrast or sludge prior to LAAC was reported [24,25]. This method could be included in diagnostic and therapeutic approaches in patients with LAAT; however, more data, especially of its safety, are needed.
All authors report favorable data on PLAAC of LAAT from a periprocedural perspective and from midterm follow-ups. Therefore, considering our experience and data from two previous papers [5,10], a multicenter, international, and preferably randomized prospective study should be planned comparing the pharmacological therapy of LAAT irresponsive to optimal anticoagulation to the invasive closure of thrombi inside of LAA.
Important limitations of our analysis are the small sample of the study population and the retrospective data analysis. Additionally, as we did not perform preprocedural and postprocedural cerebral imaging, post-PLAAC silent embolic events cannot be excluded. Due to the retrospective nature of the study, differences in diagnostics and therapy between the centers exist.
5. Conclusions
Left atrial appendage thrombus irresponsive to antithrombotic therapy might be effectively treated with percutaneous closure, including in patients with prior mechanical-valve implantations. Percutaneous left atrial appendage occluders may be safely implanted in LAAT patients even if difficult intraprocedural conditions are met, including direct contact between thrombus and occluding device.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/10/4/726/s1. Video S1: left atrial appendage thrombus, Video S2: contact between occluder and left atrial appendage thrombus during device insertion, Figure S1: left atrial appendage remnant with thrombus inside, Table S1: clinical and procedural details of each patient.
Click here for additional data file.
Author Contributions
Conceptualization, K.K.; methodology, K.K., P.J., M.G., Z.K.; software, not applicable; validation, not applicable; formal analysis, I.C., P.P.; investigation, K.K., P.J., W.S., R.P., Z.K., A.B.-S., A.M., M.G.; resources, not applicable; data curation, K.K., I.C.; writing—original-draft preparation, K.K.; writing—review and editing, I.C., R.P., M.G.; visualization, P.J., M.G.; supervision, P.P., Z.K, J.K.W.; project administration, K.K.; funding acquisition, not applicable. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Medical University of Lodz, Poland (RNN/223/18/KE; 12 June 2018).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The majority of the data presented in this study are available in Supplementary Table S1. Further data presented in this study are available on request from the corresponding author.
Conflicts of Interest
Iwona Cygankiewicz, Paweł Ptaszyński, Rafał Płaksej, Anna Babicz-Sadowska, and Agata Markiewicz declare no conflict of interest. The following conflicts of interest are declared: Krzysztof Kaczmarek—proctoring and educational fees from Abbott Co., IL, USA; Witold Streb—proctoring fees from Abbott Co., IL, USA; Piotr Jakubowski—proctoring and educational fees from Abbott Co., IL, USA; Zbigniew Kalarus—proctoring fees from Abbott Co., IL, USA, Marek Grygier—proctoring, research and educational fees from Boston Scientific Co., MA, USA; Advisory Board Member Boston Scientific Co., MA, USA. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Figure 1 Measurement of percentage of left atrial appendage volume occupied by thrombus in transesophageal echocardiography (TEE) (Supplementary Video S1). A1 and A2, Areas 1 and 2; C1 and C2, Circumferences 1 and 2; R, ratio A1/A2.
Figure 2 Occluder in contact with left atrial appendage thrombus.
jcm-10-00726-t001_Table 1Table 1 Clinical characteristics of study population.
Clinical Characteristics
Age, years 68.2 ± 13.9
Sex, male 11 (64.7%)
CHA2DS2VASC 4.7 ± 1.9
CHA2DS2VASC > 3 14 (82.4%)
HASBLED 3 (0–5)
HASBLED > 2 10 (58.8%)
Coronary artery disease 7 (41.2%)
Arterial hypertension 14 (82.4%)
Diabetes 7 (41.2%)
Renal failure 5 (29.4%)
Heart failure
HFrEF
HFmEF 9 (52.9%)
6 (35.3%)
3 (17.6%)
Left ventricular ejection fraction (%) 43.7 ± 14.7
Atrial fibrillation/flutter
Paroxysmal
Persistent
Permanent 17 (100%)
3 (17.6%)
6 (35.3%)
8 (47.1%)
Previous stroke
Ischemic
Hemorrhagic 10 (58.8%)
8 (47.1%)
2 (11.8%)
Previous cardiac surgery
Biological prosthesis
Mechanical prosthesis
LAA excision 6 (35.5%)
1 (5.9%)
4 (23.5%)
1 (5.9%)
Previous implanted pacemaker/ICD device 4 (23.5%)
Anticoagulant or antiplatelet treatment before LAA procedure:
VKA
DOAC
ASA
Enoxaparin 17 (100%)
10 (58.8%)
5 (29.4%)
1 (5.9%)
1 (5.9%)
Antithrombotic therapy intensification before LAA procedure:
Indication for PLAAC
Contraindication for OAC
Stroke on OAC
LAA thrombus on OAC/APT 12 (70.6%)
8 (47.1%)
4 (23.5%)
5 (29.4%)
HFrEF, heart failure with reduced ejection fraction; HF, heart failure with midrange ejection fraction; ICD, implantable cardioverter-defibrillator; VKA, Vitamin K antagonists; DOAC, direct oral anticoagulants; ASA, acetylsalicylic acid; OAC, oral anticoagulant; LAA, left atrial appendage; APT, antiplatelet therapy.
jcm-10-00726-t002_Table 2Table 2 Echocardiographic characteristics of study population.
Echocardiographic Parameters
LAA anatomical type
Cauliflower
Windsock
Chicken wing
Cactus
Undetermined (remnant of LAA)
7 (41.2%)
4 (23.5%)
3 (17.6%)
2 (11.8%)
1 (5.9%)
LAA orifice diameter (mm)
Longest
Shortest
22.5 ± 4.2
18.6 ± 2.5
LAA depth (mm) 34.0 ± 6.3
LAA orifice eccentricity index 0.12 (0.05–0.45)
LAA thrombus location (portion)
½ proximal
½ distal
0 (0.0%)
17 (100%)
Thrombus burden area within LAA/LAA area (%) 22.1 ± 5.6
LAA, left atrial appendage.
jcm-10-00726-t003_Table 3Table 3 Characteristics of percutaneous left atrial appendage closure procedures.
Cardiac rhythm during procedure
Sinus rhythm
Atrial fibrillation/flutter
2 (11.8%)
15 (88.2%)
Anesthesia
Conscious sedation
General anesthesia
17 (100%)
0 (0.0%)
Implanted device
Amplatzer amulet
Watchman
Watchman FLX
13 (76.5%)
2 (11.8%)
2 (11.8%)
Device size (mm) 27 (18–34)
Device mean oversize (mm) 6.3 ± 1.9
Device mean oversize (%) 15.5 ± 3.9
Device deployment attempts
1 attempt
>1 attempt 1 (1–4)
11 (64.7%)
6 (35.3%)
Auriculography 5 (29.4%)
Procedural complication 0 (0.0%)
LAAC success
Device success
Technical success
Procedural success
17 (100%)
16 (94.1%)
16 (94.1%)
TEE duration (min) 46 (20–90)
Skin–skin procedure duration (min) 40 (30–80)
LAAC, left atrial appendage closure; LAA, left atrial appendage; TEE, transesophageal echocardiography. | Oral | DrugAdministrationRoute | CC BY | 33673147 | 19,055,045 | 2021-02-12 |
What was the administration route of drug 'BACLOFEN'? | Botulinum Neurotoxin Injections in Childhood Opisthotonus.
Opisthotonus refers to abnormal axial extension and arching of the trunk produced by excessive contractions of the paraspinal muscles. In childhood, the abnormal posture is most often related to dystonia in the setting of hypoxic injury or a number of other acquired and genetic etiologies. The condition is often painful, interferes with ambulation and quality of life, and is challenging to treat. Therapeutic options include oral benzodiazepines, oral and intrathecal baclofen, botulinum neurotoxin injections, and deep brain stimulation. Management of opisthotonus within the pediatric population has not been systematically reviewed. Here, we describe a series of seven children who presented to our institution with opisthotonus in whom symptom relief was achieved following administration of botulinum neurotoxin injections.
1. Introduction
Opisthotonus, derived from the Greek “opistho” meaning behind and “tonos” meaning tone, was described by Nayler in 1803 within the context of tetanus as “such rigid contractions of those of the back, as to draw his head forcibly backwards at the same that his chest was considerably elevated” and described his expression as “bearing the strongest possible marks of the agony he suffered” [1]. Later, it was described by Charcot in 1887 as “arc de cercle”, or arching of the body such that the patient is suspended above the bed by the head and the heels [2]. Charcot’s description of abnormal posture was in the context of hysteroepileptic spells, later classified as psychogenic or functional dystonia [3,4]. Opisthotonus involves forceful axial extension of the trunk and also neck (retrocollis), caused by involuntary contractions of the paraspinal muscles, often associated with dystonic posturing of arms and legs (Figure 1) [5]. Although most frequently attributed to dystonia, there are many causes of opisthotonus that have been identified (Table 1). While in adults, the most common cause of opisthotonus is tardive dystonia [6], typically associated with adduction of the shoulders and extension/pronation of the arms, the most common causes of childhood opisthotonus are perinatal hypoxic-ischemic injury, and genetic/metabolic disorders which often present as a cerebral palsy phenotype [5].
Opisthotonus represents one of several abnormal axial skeletal abnormalities en-countered in adult and pediatric populations, also including camptocormia, scoliosis, and other postural abnormalities [7,8]. It can be persistent and severe, occurring in-termittently or for sustained periods throughout the day, and when it presents as such, it is incompatible with living comfortably at home. If left untreated, many patients with these axial abnormalities develop contractures, fixed deformities due to shorten-ing of muscles and tendons. In some cases of dystonic opisthotonus, the intense con-tractions of the paraspinal muscles can lead to dystonic storm (also known as status dystonicus) [9,10]. This potentially fatal condition is characterized by persistent, worsening dystonia associated with interference with sleep as well at least one meta-bolic disturbance: (1) fever not due to infectious etiology, (2) abnormal electrolytes, (3) elevated CK ≥ 1000, (4) myoglobinuria [10]. Although relatively rare, dystonic storm is a life-threatening emergency and its complications can lead to respiratory failure, re-nal failure, or even death [10,11].
toxins-13-00137-t001_Table 1 Table 1 Etiologies of opisthotonus.
Acquired Genetic/Metabolic
Hypoxic injury Krabbe disease [12]
Perinatal asphyxia [5] Gaucher disease [13]
Near-drowning [5] Adenylosuccinate lyase deficiency [14]
Cardiac/respiratory arrest [2] Lesch-Nyhan syndrome [15]
Traumatic asphyxia [2] Glutaric aciduria [16]
Infectious/Post-infectious Maple syrup urine disease [17]
Meningitis [18,19] Monoamine neurotransmitter defect [20,21]
Encephalitis [22,23] Wilson disease [24]
Tetanus [1,25,26,27,28] Neurodegeneration with brain iron accumulation (NBIA), e.g., pantothenate kinase-associated neurodegeneration (PKAN) [15]
Rabies [29] Other genetic disorders 1 [21,30]
Neurosyphilis [31]
Cerebral malaria [12]
Toxins/elevated toxic metabolites
Kernicterus [12]
Strychnine [32]
Phencyclidine [32]
Phenothiazines [32]
Propofol [33,34]
Methoxphenidine [35]
Neonatal caffeine overdose [32]
Increased Intracranial Pressure
Subarachnoid hemorrhage [5]
Intracerebral hemorrhage [5]
Hydrocephalus [36]
Mass/Tumor [36]
Autoimmune
Stiff-person syndrome [37]
Anti-NMDA receptor encephalitis [22]
Other
Functional (psychogenic) dystonia [3,4,38]
Tardive dystonia [6,30,39,40,41,42,43]
Malignant catatonia [29]
Brainstem/cerebellar malformation [44]
Epilepsy [12]
1 Any genetic syndromes with prominent dystonia have the potential to manifest opisthotonus.
Treatment of opisthotonus is multifactorial, first targeting reversible causes such as discontinuation of the offending dopamine-receptor blocking drugs that may be causing acute or tardive dystonia, and the consideration of disease-specific therapies. In most cases, no such interventions are available, and supportive measures are employed, often consisting of a tiered approach beginning with oral medications (benzodiazepines, baclofen, and anticholinergics), and in more refractory cases requiring intravenous benzodiazepines for exacerbations and/or surgical interventions such as intrathecal baclofen pump or deep brain stimulation [45,46,47].
Over the past half-century, botulinum neurotoxin (BoNT) has emerged as one of the most versatile therapeutics in neurologic and non-neurologic disorders [48]. There are dozens of indications in the field of movement disorders alone [49], including treatment of spasticity and a variety of abnormal involuntary movements such as tremor, tics, hemifacial spasm, and most commonly focal/segmental dystonia [50]. In children with refractory generalized dystonia, areas of the body that are dispropor-tionately affected, or in which the dystonia causes a great deal of discomfort, can also be selectively targeted with BoNT. It acts primarily by inhibiting the release of acetyl-choline from the presynaptic nerve terminal through interfering with fusion of the synaptic vesicle with the plasma membrane at the level of the neuromuscular junction.
Here, we describe a series of children suffering from opisthotonus whose symptoms were adequately controlled using BoNT injections.
2. Results
We evaluated seven patients (four female), age range 15 months to 13 years, all with opisthotonus, who were treated at our institution with BoNT (Table 2). Etiologies varied, with three due to identified genetic causes including pantothenate kinase asso-ciated neurodegeneration (PKAN), hypomyelinating leukodystrophy-14, CASK-related disorder, and a single case with undetermined, likely genetic etiology with normal im-aging and lack of other risk factors. Three of the patients presented with dystonic storm.
All patients were also treated with oral clonazepam and baclofen with partial though insufficient benefit. Two patients received trials of oral clonidine which was limited by excessive somnolence and hypotension as well as no clear improvement in opisthotonus, and therefore discontinued in both patients. One patient had presumed tardive dystonia and akathisia and was also treated with tetrabenazine, which was helpful for the akathisia, but with no clear improvement in the axial dystonia. The three patients who presented with dystonic storm were also managed with intrave-nous sedation, which led to control of symptoms until attempting to wean the intra-venous therapies, at which time posturing worsened.
Sites and dosing were chosen based on the involved muscles and estimated muscle mass and force of muscle contraction. All patients received onabotulinumtoxinA injec-tions in the paraspinal muscles and six patients received injections at other sites in-volved, with the most common being splenius capitis for management of concurrent retrocollis (five out of seven patients) (Table 3). Dosing to the paraspinal muscles ranged between 120 to 300 units (average 215.7 units) and were divided into three to five injections on each side. Total units administered ranged between 150 to 650 units (average 341.4 units). Although the dosing regimen was not planned using weight-based calculations, total units administered per kilogram for these patients ranged from 16.7 to 23.8 U/kg (average 19.6 U/kg).
All patients showed an improvement in opisthotonus within 3–14 days (average 6.1 days). Arching improved notably on examination of each child, and improvement was deemed to be of a meaningful and sufficient degree by caregivers of all injected children. There were no adverse effects with the exception of one patient who experi-enced neck extensor weakness, which resolved over a period of weeks and did not re-cur with subsequent injections omitting the splenius capitis. Four of seven patients re-quired repeat injections approximately three months following initial injections. No patient in this series has required escalation of treatment to involve surgical manage-ment of tone thus far. See Video S1 and Video S2 for illustrative cases before and after treatment.
3. Discussion
This is the first report of childhood opisthotonus successfully treated with BoNT injections. The first description of adequate treatment of opisthotonus was by Nayler in 1803 in which he treated a 36-year-old man suffering from presumed tetanus fol-lowing a farming injury. Nayler quickly began treatment of the man which included “bladders of warm water to his feet, forty drops of laudanum to be taken every four hours in a camphorated mixture with tincture of castor.” When there was no im-provement, he also ordered “wine freely, to the amount of a bottle in the day with a strong decoction of the bark and valerian, at the same time a liniment well charged with opium was rubbed into his chest and limbs twice a day” [1]. After some period of time had passed, the patient’s symptoms eventually improved.
In 1877, another patient was reported with opisthotonus, as a result of an empy-ema following a traumatic brain injury. He was treated with “a mixture containing eighty grains of chloral-hydrate, half a drachm of extractum opii liquidum, and cam-phor” [51].
Since then, the approach to treatment of opisthotonus has been largely empirical and unsuccessful, typically involving a trial of several oral medications [30]. It was not until 1991, when Narayan and colleagues treated a patient with severe opisthotonus and generalized dystonia suffering from dystonic storm with urgent intrathecal baclo-fen that the use of more invasive measures became more common [47].
Further reports of surgical management of opisthotonus include deep brain stim-ulation [46] and intrathecal baclofen [5,13,47], each with clinical benefit. However, not all patients are good surgical candidates, the procedures are not without risks, both in-traoperatively and long-term, and there can be insufficient benefit from either surgical treatment.
Our series of patients provides evidence that there is a role for BoNT injections in combination with pharmacotherapy, and prior to or supplemental to surgical inter-ventions, in children with axial dystonia, including opisthotonus. Retrospective studies have reported doses of up to 15–20 U/kg, and total doses of 800–1200 U have been safe; however, there have not been any large prospective studies in children determining a true upper dose limit [52,53,54,55]. Furthermore, the treatment was well-tolerated within this group, with no serious adverse events, and only a single case of transient neck ex-tensor weakness. None of the seven patients treated with injections required surgical treatment.
The three patients who did not require repeat injections in the months immedi-ately following initial injections may not have needed them due to the fluctuating na-ture of their underlying dystonia. This was evidenced by the eventual decrease in pos-turing even in sites not injected. Other potential reasons for improvement of dystonia also include management of pain, constipation, underlying infection, or other potential triggers of worsening dystonia, as well as maturing neural networks within the young-er population. Repeat injections remain an option, should dystonia become exacerbat-ed again in the future.
Limitations of this study include its retrospective, open-label design. Injections were performed using anatomic landmarks, without electromyogram or ultrasound guidance. Moreover, there is no objective scoring system that is clearly applicable to the pediatric population, though by subjective report, video (Video S1, Video S2), and clinical documentation, there was clear improvement of opisthotonus in these patients.
4. Conclusions
Despite the retrospective, small, and open-label design, our study provides evidence that BoNT injections into paraspinal muscles ameliorates childhood opisthotonus without serious adverse effects. This treatment should be added to the armamentaria of treatment options for this form of axial dystonia, particularly in cases refractory to oral medications. Of note, over half of the patients reviewed here are believed to have a genetic etiology for their opisthotonus.
5. Materials and Methods
Here, we describe seven patients who presented to our center for management of opisthotonus and were treated with BoNT injections. Patients were followed clinically and we discussed features, dosing regimen, and outcomes through a review of clinical documentation and laboratory and radiology reports.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6651/13/2/137/s1. Video S1: Patient 1 prior to botulinum neurotoxin injections and nine days following injections. Video S2: Patient 2 prior to botulinum neurotoxin injections and five days following injections.
Click here for additional data file.
Author Contributions
Conceptualization and methodology, M.H. and M.P.; writing—original draft preparation, M.H.; writing—review and editing, supervision, M.P. and J.J. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, no IRB was required for preparation of this case series, ethical guidelines were followed to assure patient privacy was maintained. Written consent from patient guardians was obtained prior to obtaining video and images for purposes of education within a medical peer reviewed journal.
Informed Consent Statement
Informed consent was obtained from all patient guardians and obtained prior to acquiring video and images.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available to maintain patient privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Illustrative photographs of opisthotonus of patient 4 prior to receiving treatment displaying characteristic axial extension of the trunk and neck.
toxins-13-00137-t002_Table 2 Table 2 Characteristics of patients undergoing treatment of opisthotonus.
Patient Sex Age Genetic vs. Acquired Etiology of Opisthotonus Weight (kg) History of Dystonic Storm
1 M 15 mo Acquired—Post-infectious 7.3 Yes
2 F 26 mo Genetic—Hypomyelinating leukodystrophy-14 8.5 Yes
3 M 8 yr Genetic—NBIA/PKAN 23.7 No
4 F 10 yr Acquired—Perinatal HIE 25.7 Yes
5 F 3 yr Genetic—presumed 14.7 No
6 M 26 mo Genetic—CASK-related disorder 12.2 No
7 F 13 yr Acquired—Tardive dystonia 34.4 No
M = male, F = female, NBIA = neurodegeneration with brain iron accumulation, PKAN = pantothenate kinase associated neurodegeneration, HIE = hypoxic-ischemic insult, CASK = calcium/calmodulin-dependent serine protein kinase gene.
toxins-13-00137-t003_Table 3 Table 3 Botulinum neurotoxin dosing regimens for patients with prominent opisthotonus.
Patient Paraspinal Dosing (Units) Other Muscles Injected Total Dose (Units) Latency (Days) Adverse Effects Duration of Benefit (Weeks) Outcome Repeat Injections Required Other Treatments 1
1 150 None 150 3 None 12 Complete resolution of opisthotonus during maximal effect Yes Baclofen, clonazepam, diazepam, lorazepam, clonidine
2 120 Splenius capitis 170 5 None 14 Complete resolution of opisthotonus during maximal effect Yes Clonazepam, midazolam, dexmedetomidine, baclofen
3 260 Triceps brachii, pectoralis major, gluteus maximus 400 14 None 14–16 Complete resolution of opisthotonus during maximal effect Yes Clonazepam, baclofen, tetrabenazine
4 300 Splenius capitis, sternocleidomastoid 430 6 None 12–16 Complete resolution of opisthotonus during maximal effect No 2 Clonazepam, lorazepam, diazepam, baclofen, carbidopa/levodopa, gabapentin, dexmedetomidine, morphine
5 160 Splenius capitis, gastrocnemeus, rectus femoris 300 7 None 10 Complete resolution of opisthotonus during maximal effect No 3 Clonazepam, baclofen, phenol injections
6 220 Splenius capitis 290 3 None 12–14 Complete resolution of opisthotonus during maximal effect with gradual wearing off, remaining dystonia not impairing No Clonazepam, baclofen
7 300 Splenius capitis, gastrocnemeus 650 5 Neck weakness 2 16 Complete resolution of opisthotonus during maximal effect Yes Clonazepam, lorazepam, diazepam, trihexyphenidyl, baclofen, haloperidol, tetrabenazine, guanfacine, clonidine, carbidopa/levodopa, propranolol, carbamazepine, topiramate, duloxetine, cyclobenzaprine, methocarbamol, morphine, ketamine
1 Includes treatments tried by previous providers/institutions. 2 Subsequent injections omitted splenius capitis with resolution of symptoms 3 Increased posturing after wearing off was managed with increased dose of oral clonazepam 3 and oral baclofen.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Oral | DrugAdministrationRoute | CC BY | 33673369 | 19,648,953 | 2021-02-12 |
What was the administration route of drug 'CLONAZEPAM'? | Botulinum Neurotoxin Injections in Childhood Opisthotonus.
Opisthotonus refers to abnormal axial extension and arching of the trunk produced by excessive contractions of the paraspinal muscles. In childhood, the abnormal posture is most often related to dystonia in the setting of hypoxic injury or a number of other acquired and genetic etiologies. The condition is often painful, interferes with ambulation and quality of life, and is challenging to treat. Therapeutic options include oral benzodiazepines, oral and intrathecal baclofen, botulinum neurotoxin injections, and deep brain stimulation. Management of opisthotonus within the pediatric population has not been systematically reviewed. Here, we describe a series of seven children who presented to our institution with opisthotonus in whom symptom relief was achieved following administration of botulinum neurotoxin injections.
1. Introduction
Opisthotonus, derived from the Greek “opistho” meaning behind and “tonos” meaning tone, was described by Nayler in 1803 within the context of tetanus as “such rigid contractions of those of the back, as to draw his head forcibly backwards at the same that his chest was considerably elevated” and described his expression as “bearing the strongest possible marks of the agony he suffered” [1]. Later, it was described by Charcot in 1887 as “arc de cercle”, or arching of the body such that the patient is suspended above the bed by the head and the heels [2]. Charcot’s description of abnormal posture was in the context of hysteroepileptic spells, later classified as psychogenic or functional dystonia [3,4]. Opisthotonus involves forceful axial extension of the trunk and also neck (retrocollis), caused by involuntary contractions of the paraspinal muscles, often associated with dystonic posturing of arms and legs (Figure 1) [5]. Although most frequently attributed to dystonia, there are many causes of opisthotonus that have been identified (Table 1). While in adults, the most common cause of opisthotonus is tardive dystonia [6], typically associated with adduction of the shoulders and extension/pronation of the arms, the most common causes of childhood opisthotonus are perinatal hypoxic-ischemic injury, and genetic/metabolic disorders which often present as a cerebral palsy phenotype [5].
Opisthotonus represents one of several abnormal axial skeletal abnormalities en-countered in adult and pediatric populations, also including camptocormia, scoliosis, and other postural abnormalities [7,8]. It can be persistent and severe, occurring in-termittently or for sustained periods throughout the day, and when it presents as such, it is incompatible with living comfortably at home. If left untreated, many patients with these axial abnormalities develop contractures, fixed deformities due to shorten-ing of muscles and tendons. In some cases of dystonic opisthotonus, the intense con-tractions of the paraspinal muscles can lead to dystonic storm (also known as status dystonicus) [9,10]. This potentially fatal condition is characterized by persistent, worsening dystonia associated with interference with sleep as well at least one meta-bolic disturbance: (1) fever not due to infectious etiology, (2) abnormal electrolytes, (3) elevated CK ≥ 1000, (4) myoglobinuria [10]. Although relatively rare, dystonic storm is a life-threatening emergency and its complications can lead to respiratory failure, re-nal failure, or even death [10,11].
toxins-13-00137-t001_Table 1 Table 1 Etiologies of opisthotonus.
Acquired Genetic/Metabolic
Hypoxic injury Krabbe disease [12]
Perinatal asphyxia [5] Gaucher disease [13]
Near-drowning [5] Adenylosuccinate lyase deficiency [14]
Cardiac/respiratory arrest [2] Lesch-Nyhan syndrome [15]
Traumatic asphyxia [2] Glutaric aciduria [16]
Infectious/Post-infectious Maple syrup urine disease [17]
Meningitis [18,19] Monoamine neurotransmitter defect [20,21]
Encephalitis [22,23] Wilson disease [24]
Tetanus [1,25,26,27,28] Neurodegeneration with brain iron accumulation (NBIA), e.g., pantothenate kinase-associated neurodegeneration (PKAN) [15]
Rabies [29] Other genetic disorders 1 [21,30]
Neurosyphilis [31]
Cerebral malaria [12]
Toxins/elevated toxic metabolites
Kernicterus [12]
Strychnine [32]
Phencyclidine [32]
Phenothiazines [32]
Propofol [33,34]
Methoxphenidine [35]
Neonatal caffeine overdose [32]
Increased Intracranial Pressure
Subarachnoid hemorrhage [5]
Intracerebral hemorrhage [5]
Hydrocephalus [36]
Mass/Tumor [36]
Autoimmune
Stiff-person syndrome [37]
Anti-NMDA receptor encephalitis [22]
Other
Functional (psychogenic) dystonia [3,4,38]
Tardive dystonia [6,30,39,40,41,42,43]
Malignant catatonia [29]
Brainstem/cerebellar malformation [44]
Epilepsy [12]
1 Any genetic syndromes with prominent dystonia have the potential to manifest opisthotonus.
Treatment of opisthotonus is multifactorial, first targeting reversible causes such as discontinuation of the offending dopamine-receptor blocking drugs that may be causing acute or tardive dystonia, and the consideration of disease-specific therapies. In most cases, no such interventions are available, and supportive measures are employed, often consisting of a tiered approach beginning with oral medications (benzodiazepines, baclofen, and anticholinergics), and in more refractory cases requiring intravenous benzodiazepines for exacerbations and/or surgical interventions such as intrathecal baclofen pump or deep brain stimulation [45,46,47].
Over the past half-century, botulinum neurotoxin (BoNT) has emerged as one of the most versatile therapeutics in neurologic and non-neurologic disorders [48]. There are dozens of indications in the field of movement disorders alone [49], including treatment of spasticity and a variety of abnormal involuntary movements such as tremor, tics, hemifacial spasm, and most commonly focal/segmental dystonia [50]. In children with refractory generalized dystonia, areas of the body that are dispropor-tionately affected, or in which the dystonia causes a great deal of discomfort, can also be selectively targeted with BoNT. It acts primarily by inhibiting the release of acetyl-choline from the presynaptic nerve terminal through interfering with fusion of the synaptic vesicle with the plasma membrane at the level of the neuromuscular junction.
Here, we describe a series of children suffering from opisthotonus whose symptoms were adequately controlled using BoNT injections.
2. Results
We evaluated seven patients (four female), age range 15 months to 13 years, all with opisthotonus, who were treated at our institution with BoNT (Table 2). Etiologies varied, with three due to identified genetic causes including pantothenate kinase asso-ciated neurodegeneration (PKAN), hypomyelinating leukodystrophy-14, CASK-related disorder, and a single case with undetermined, likely genetic etiology with normal im-aging and lack of other risk factors. Three of the patients presented with dystonic storm.
All patients were also treated with oral clonazepam and baclofen with partial though insufficient benefit. Two patients received trials of oral clonidine which was limited by excessive somnolence and hypotension as well as no clear improvement in opisthotonus, and therefore discontinued in both patients. One patient had presumed tardive dystonia and akathisia and was also treated with tetrabenazine, which was helpful for the akathisia, but with no clear improvement in the axial dystonia. The three patients who presented with dystonic storm were also managed with intrave-nous sedation, which led to control of symptoms until attempting to wean the intra-venous therapies, at which time posturing worsened.
Sites and dosing were chosen based on the involved muscles and estimated muscle mass and force of muscle contraction. All patients received onabotulinumtoxinA injec-tions in the paraspinal muscles and six patients received injections at other sites in-volved, with the most common being splenius capitis for management of concurrent retrocollis (five out of seven patients) (Table 3). Dosing to the paraspinal muscles ranged between 120 to 300 units (average 215.7 units) and were divided into three to five injections on each side. Total units administered ranged between 150 to 650 units (average 341.4 units). Although the dosing regimen was not planned using weight-based calculations, total units administered per kilogram for these patients ranged from 16.7 to 23.8 U/kg (average 19.6 U/kg).
All patients showed an improvement in opisthotonus within 3–14 days (average 6.1 days). Arching improved notably on examination of each child, and improvement was deemed to be of a meaningful and sufficient degree by caregivers of all injected children. There were no adverse effects with the exception of one patient who experi-enced neck extensor weakness, which resolved over a period of weeks and did not re-cur with subsequent injections omitting the splenius capitis. Four of seven patients re-quired repeat injections approximately three months following initial injections. No patient in this series has required escalation of treatment to involve surgical manage-ment of tone thus far. See Video S1 and Video S2 for illustrative cases before and after treatment.
3. Discussion
This is the first report of childhood opisthotonus successfully treated with BoNT injections. The first description of adequate treatment of opisthotonus was by Nayler in 1803 in which he treated a 36-year-old man suffering from presumed tetanus fol-lowing a farming injury. Nayler quickly began treatment of the man which included “bladders of warm water to his feet, forty drops of laudanum to be taken every four hours in a camphorated mixture with tincture of castor.” When there was no im-provement, he also ordered “wine freely, to the amount of a bottle in the day with a strong decoction of the bark and valerian, at the same time a liniment well charged with opium was rubbed into his chest and limbs twice a day” [1]. After some period of time had passed, the patient’s symptoms eventually improved.
In 1877, another patient was reported with opisthotonus, as a result of an empy-ema following a traumatic brain injury. He was treated with “a mixture containing eighty grains of chloral-hydrate, half a drachm of extractum opii liquidum, and cam-phor” [51].
Since then, the approach to treatment of opisthotonus has been largely empirical and unsuccessful, typically involving a trial of several oral medications [30]. It was not until 1991, when Narayan and colleagues treated a patient with severe opisthotonus and generalized dystonia suffering from dystonic storm with urgent intrathecal baclo-fen that the use of more invasive measures became more common [47].
Further reports of surgical management of opisthotonus include deep brain stim-ulation [46] and intrathecal baclofen [5,13,47], each with clinical benefit. However, not all patients are good surgical candidates, the procedures are not without risks, both in-traoperatively and long-term, and there can be insufficient benefit from either surgical treatment.
Our series of patients provides evidence that there is a role for BoNT injections in combination with pharmacotherapy, and prior to or supplemental to surgical inter-ventions, in children with axial dystonia, including opisthotonus. Retrospective studies have reported doses of up to 15–20 U/kg, and total doses of 800–1200 U have been safe; however, there have not been any large prospective studies in children determining a true upper dose limit [52,53,54,55]. Furthermore, the treatment was well-tolerated within this group, with no serious adverse events, and only a single case of transient neck ex-tensor weakness. None of the seven patients treated with injections required surgical treatment.
The three patients who did not require repeat injections in the months immedi-ately following initial injections may not have needed them due to the fluctuating na-ture of their underlying dystonia. This was evidenced by the eventual decrease in pos-turing even in sites not injected. Other potential reasons for improvement of dystonia also include management of pain, constipation, underlying infection, or other potential triggers of worsening dystonia, as well as maturing neural networks within the young-er population. Repeat injections remain an option, should dystonia become exacerbat-ed again in the future.
Limitations of this study include its retrospective, open-label design. Injections were performed using anatomic landmarks, without electromyogram or ultrasound guidance. Moreover, there is no objective scoring system that is clearly applicable to the pediatric population, though by subjective report, video (Video S1, Video S2), and clinical documentation, there was clear improvement of opisthotonus in these patients.
4. Conclusions
Despite the retrospective, small, and open-label design, our study provides evidence that BoNT injections into paraspinal muscles ameliorates childhood opisthotonus without serious adverse effects. This treatment should be added to the armamentaria of treatment options for this form of axial dystonia, particularly in cases refractory to oral medications. Of note, over half of the patients reviewed here are believed to have a genetic etiology for their opisthotonus.
5. Materials and Methods
Here, we describe seven patients who presented to our center for management of opisthotonus and were treated with BoNT injections. Patients were followed clinically and we discussed features, dosing regimen, and outcomes through a review of clinical documentation and laboratory and radiology reports.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6651/13/2/137/s1. Video S1: Patient 1 prior to botulinum neurotoxin injections and nine days following injections. Video S2: Patient 2 prior to botulinum neurotoxin injections and five days following injections.
Click here for additional data file.
Author Contributions
Conceptualization and methodology, M.H. and M.P.; writing—original draft preparation, M.H.; writing—review and editing, supervision, M.P. and J.J. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, no IRB was required for preparation of this case series, ethical guidelines were followed to assure patient privacy was maintained. Written consent from patient guardians was obtained prior to obtaining video and images for purposes of education within a medical peer reviewed journal.
Informed Consent Statement
Informed consent was obtained from all patient guardians and obtained prior to acquiring video and images.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available to maintain patient privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Illustrative photographs of opisthotonus of patient 4 prior to receiving treatment displaying characteristic axial extension of the trunk and neck.
toxins-13-00137-t002_Table 2 Table 2 Characteristics of patients undergoing treatment of opisthotonus.
Patient Sex Age Genetic vs. Acquired Etiology of Opisthotonus Weight (kg) History of Dystonic Storm
1 M 15 mo Acquired—Post-infectious 7.3 Yes
2 F 26 mo Genetic—Hypomyelinating leukodystrophy-14 8.5 Yes
3 M 8 yr Genetic—NBIA/PKAN 23.7 No
4 F 10 yr Acquired—Perinatal HIE 25.7 Yes
5 F 3 yr Genetic—presumed 14.7 No
6 M 26 mo Genetic—CASK-related disorder 12.2 No
7 F 13 yr Acquired—Tardive dystonia 34.4 No
M = male, F = female, NBIA = neurodegeneration with brain iron accumulation, PKAN = pantothenate kinase associated neurodegeneration, HIE = hypoxic-ischemic insult, CASK = calcium/calmodulin-dependent serine protein kinase gene.
toxins-13-00137-t003_Table 3 Table 3 Botulinum neurotoxin dosing regimens for patients with prominent opisthotonus.
Patient Paraspinal Dosing (Units) Other Muscles Injected Total Dose (Units) Latency (Days) Adverse Effects Duration of Benefit (Weeks) Outcome Repeat Injections Required Other Treatments 1
1 150 None 150 3 None 12 Complete resolution of opisthotonus during maximal effect Yes Baclofen, clonazepam, diazepam, lorazepam, clonidine
2 120 Splenius capitis 170 5 None 14 Complete resolution of opisthotonus during maximal effect Yes Clonazepam, midazolam, dexmedetomidine, baclofen
3 260 Triceps brachii, pectoralis major, gluteus maximus 400 14 None 14–16 Complete resolution of opisthotonus during maximal effect Yes Clonazepam, baclofen, tetrabenazine
4 300 Splenius capitis, sternocleidomastoid 430 6 None 12–16 Complete resolution of opisthotonus during maximal effect No 2 Clonazepam, lorazepam, diazepam, baclofen, carbidopa/levodopa, gabapentin, dexmedetomidine, morphine
5 160 Splenius capitis, gastrocnemeus, rectus femoris 300 7 None 10 Complete resolution of opisthotonus during maximal effect No 3 Clonazepam, baclofen, phenol injections
6 220 Splenius capitis 290 3 None 12–14 Complete resolution of opisthotonus during maximal effect with gradual wearing off, remaining dystonia not impairing No Clonazepam, baclofen
7 300 Splenius capitis, gastrocnemeus 650 5 Neck weakness 2 16 Complete resolution of opisthotonus during maximal effect Yes Clonazepam, lorazepam, diazepam, trihexyphenidyl, baclofen, haloperidol, tetrabenazine, guanfacine, clonidine, carbidopa/levodopa, propranolol, carbamazepine, topiramate, duloxetine, cyclobenzaprine, methocarbamol, morphine, ketamine
1 Includes treatments tried by previous providers/institutions. 2 Subsequent injections omitted splenius capitis with resolution of symptoms 3 Increased posturing after wearing off was managed with increased dose of oral clonazepam 3 and oral baclofen.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Oral | DrugAdministrationRoute | CC BY | 33673369 | 19,648,953 | 2021-02-12 |
What was the administration route of drug 'CLONIDINE'? | Botulinum Neurotoxin Injections in Childhood Opisthotonus.
Opisthotonus refers to abnormal axial extension and arching of the trunk produced by excessive contractions of the paraspinal muscles. In childhood, the abnormal posture is most often related to dystonia in the setting of hypoxic injury or a number of other acquired and genetic etiologies. The condition is often painful, interferes with ambulation and quality of life, and is challenging to treat. Therapeutic options include oral benzodiazepines, oral and intrathecal baclofen, botulinum neurotoxin injections, and deep brain stimulation. Management of opisthotonus within the pediatric population has not been systematically reviewed. Here, we describe a series of seven children who presented to our institution with opisthotonus in whom symptom relief was achieved following administration of botulinum neurotoxin injections.
1. Introduction
Opisthotonus, derived from the Greek “opistho” meaning behind and “tonos” meaning tone, was described by Nayler in 1803 within the context of tetanus as “such rigid contractions of those of the back, as to draw his head forcibly backwards at the same that his chest was considerably elevated” and described his expression as “bearing the strongest possible marks of the agony he suffered” [1]. Later, it was described by Charcot in 1887 as “arc de cercle”, or arching of the body such that the patient is suspended above the bed by the head and the heels [2]. Charcot’s description of abnormal posture was in the context of hysteroepileptic spells, later classified as psychogenic or functional dystonia [3,4]. Opisthotonus involves forceful axial extension of the trunk and also neck (retrocollis), caused by involuntary contractions of the paraspinal muscles, often associated with dystonic posturing of arms and legs (Figure 1) [5]. Although most frequently attributed to dystonia, there are many causes of opisthotonus that have been identified (Table 1). While in adults, the most common cause of opisthotonus is tardive dystonia [6], typically associated with adduction of the shoulders and extension/pronation of the arms, the most common causes of childhood opisthotonus are perinatal hypoxic-ischemic injury, and genetic/metabolic disorders which often present as a cerebral palsy phenotype [5].
Opisthotonus represents one of several abnormal axial skeletal abnormalities en-countered in adult and pediatric populations, also including camptocormia, scoliosis, and other postural abnormalities [7,8]. It can be persistent and severe, occurring in-termittently or for sustained periods throughout the day, and when it presents as such, it is incompatible with living comfortably at home. If left untreated, many patients with these axial abnormalities develop contractures, fixed deformities due to shorten-ing of muscles and tendons. In some cases of dystonic opisthotonus, the intense con-tractions of the paraspinal muscles can lead to dystonic storm (also known as status dystonicus) [9,10]. This potentially fatal condition is characterized by persistent, worsening dystonia associated with interference with sleep as well at least one meta-bolic disturbance: (1) fever not due to infectious etiology, (2) abnormal electrolytes, (3) elevated CK ≥ 1000, (4) myoglobinuria [10]. Although relatively rare, dystonic storm is a life-threatening emergency and its complications can lead to respiratory failure, re-nal failure, or even death [10,11].
toxins-13-00137-t001_Table 1 Table 1 Etiologies of opisthotonus.
Acquired Genetic/Metabolic
Hypoxic injury Krabbe disease [12]
Perinatal asphyxia [5] Gaucher disease [13]
Near-drowning [5] Adenylosuccinate lyase deficiency [14]
Cardiac/respiratory arrest [2] Lesch-Nyhan syndrome [15]
Traumatic asphyxia [2] Glutaric aciduria [16]
Infectious/Post-infectious Maple syrup urine disease [17]
Meningitis [18,19] Monoamine neurotransmitter defect [20,21]
Encephalitis [22,23] Wilson disease [24]
Tetanus [1,25,26,27,28] Neurodegeneration with brain iron accumulation (NBIA), e.g., pantothenate kinase-associated neurodegeneration (PKAN) [15]
Rabies [29] Other genetic disorders 1 [21,30]
Neurosyphilis [31]
Cerebral malaria [12]
Toxins/elevated toxic metabolites
Kernicterus [12]
Strychnine [32]
Phencyclidine [32]
Phenothiazines [32]
Propofol [33,34]
Methoxphenidine [35]
Neonatal caffeine overdose [32]
Increased Intracranial Pressure
Subarachnoid hemorrhage [5]
Intracerebral hemorrhage [5]
Hydrocephalus [36]
Mass/Tumor [36]
Autoimmune
Stiff-person syndrome [37]
Anti-NMDA receptor encephalitis [22]
Other
Functional (psychogenic) dystonia [3,4,38]
Tardive dystonia [6,30,39,40,41,42,43]
Malignant catatonia [29]
Brainstem/cerebellar malformation [44]
Epilepsy [12]
1 Any genetic syndromes with prominent dystonia have the potential to manifest opisthotonus.
Treatment of opisthotonus is multifactorial, first targeting reversible causes such as discontinuation of the offending dopamine-receptor blocking drugs that may be causing acute or tardive dystonia, and the consideration of disease-specific therapies. In most cases, no such interventions are available, and supportive measures are employed, often consisting of a tiered approach beginning with oral medications (benzodiazepines, baclofen, and anticholinergics), and in more refractory cases requiring intravenous benzodiazepines for exacerbations and/or surgical interventions such as intrathecal baclofen pump or deep brain stimulation [45,46,47].
Over the past half-century, botulinum neurotoxin (BoNT) has emerged as one of the most versatile therapeutics in neurologic and non-neurologic disorders [48]. There are dozens of indications in the field of movement disorders alone [49], including treatment of spasticity and a variety of abnormal involuntary movements such as tremor, tics, hemifacial spasm, and most commonly focal/segmental dystonia [50]. In children with refractory generalized dystonia, areas of the body that are dispropor-tionately affected, or in which the dystonia causes a great deal of discomfort, can also be selectively targeted with BoNT. It acts primarily by inhibiting the release of acetyl-choline from the presynaptic nerve terminal through interfering with fusion of the synaptic vesicle with the plasma membrane at the level of the neuromuscular junction.
Here, we describe a series of children suffering from opisthotonus whose symptoms were adequately controlled using BoNT injections.
2. Results
We evaluated seven patients (four female), age range 15 months to 13 years, all with opisthotonus, who were treated at our institution with BoNT (Table 2). Etiologies varied, with three due to identified genetic causes including pantothenate kinase asso-ciated neurodegeneration (PKAN), hypomyelinating leukodystrophy-14, CASK-related disorder, and a single case with undetermined, likely genetic etiology with normal im-aging and lack of other risk factors. Three of the patients presented with dystonic storm.
All patients were also treated with oral clonazepam and baclofen with partial though insufficient benefit. Two patients received trials of oral clonidine which was limited by excessive somnolence and hypotension as well as no clear improvement in opisthotonus, and therefore discontinued in both patients. One patient had presumed tardive dystonia and akathisia and was also treated with tetrabenazine, which was helpful for the akathisia, but with no clear improvement in the axial dystonia. The three patients who presented with dystonic storm were also managed with intrave-nous sedation, which led to control of symptoms until attempting to wean the intra-venous therapies, at which time posturing worsened.
Sites and dosing were chosen based on the involved muscles and estimated muscle mass and force of muscle contraction. All patients received onabotulinumtoxinA injec-tions in the paraspinal muscles and six patients received injections at other sites in-volved, with the most common being splenius capitis for management of concurrent retrocollis (five out of seven patients) (Table 3). Dosing to the paraspinal muscles ranged between 120 to 300 units (average 215.7 units) and were divided into three to five injections on each side. Total units administered ranged between 150 to 650 units (average 341.4 units). Although the dosing regimen was not planned using weight-based calculations, total units administered per kilogram for these patients ranged from 16.7 to 23.8 U/kg (average 19.6 U/kg).
All patients showed an improvement in opisthotonus within 3–14 days (average 6.1 days). Arching improved notably on examination of each child, and improvement was deemed to be of a meaningful and sufficient degree by caregivers of all injected children. There were no adverse effects with the exception of one patient who experi-enced neck extensor weakness, which resolved over a period of weeks and did not re-cur with subsequent injections omitting the splenius capitis. Four of seven patients re-quired repeat injections approximately three months following initial injections. No patient in this series has required escalation of treatment to involve surgical manage-ment of tone thus far. See Video S1 and Video S2 for illustrative cases before and after treatment.
3. Discussion
This is the first report of childhood opisthotonus successfully treated with BoNT injections. The first description of adequate treatment of opisthotonus was by Nayler in 1803 in which he treated a 36-year-old man suffering from presumed tetanus fol-lowing a farming injury. Nayler quickly began treatment of the man which included “bladders of warm water to his feet, forty drops of laudanum to be taken every four hours in a camphorated mixture with tincture of castor.” When there was no im-provement, he also ordered “wine freely, to the amount of a bottle in the day with a strong decoction of the bark and valerian, at the same time a liniment well charged with opium was rubbed into his chest and limbs twice a day” [1]. After some period of time had passed, the patient’s symptoms eventually improved.
In 1877, another patient was reported with opisthotonus, as a result of an empy-ema following a traumatic brain injury. He was treated with “a mixture containing eighty grains of chloral-hydrate, half a drachm of extractum opii liquidum, and cam-phor” [51].
Since then, the approach to treatment of opisthotonus has been largely empirical and unsuccessful, typically involving a trial of several oral medications [30]. It was not until 1991, when Narayan and colleagues treated a patient with severe opisthotonus and generalized dystonia suffering from dystonic storm with urgent intrathecal baclo-fen that the use of more invasive measures became more common [47].
Further reports of surgical management of opisthotonus include deep brain stim-ulation [46] and intrathecal baclofen [5,13,47], each with clinical benefit. However, not all patients are good surgical candidates, the procedures are not without risks, both in-traoperatively and long-term, and there can be insufficient benefit from either surgical treatment.
Our series of patients provides evidence that there is a role for BoNT injections in combination with pharmacotherapy, and prior to or supplemental to surgical inter-ventions, in children with axial dystonia, including opisthotonus. Retrospective studies have reported doses of up to 15–20 U/kg, and total doses of 800–1200 U have been safe; however, there have not been any large prospective studies in children determining a true upper dose limit [52,53,54,55]. Furthermore, the treatment was well-tolerated within this group, with no serious adverse events, and only a single case of transient neck ex-tensor weakness. None of the seven patients treated with injections required surgical treatment.
The three patients who did not require repeat injections in the months immedi-ately following initial injections may not have needed them due to the fluctuating na-ture of their underlying dystonia. This was evidenced by the eventual decrease in pos-turing even in sites not injected. Other potential reasons for improvement of dystonia also include management of pain, constipation, underlying infection, or other potential triggers of worsening dystonia, as well as maturing neural networks within the young-er population. Repeat injections remain an option, should dystonia become exacerbat-ed again in the future.
Limitations of this study include its retrospective, open-label design. Injections were performed using anatomic landmarks, without electromyogram or ultrasound guidance. Moreover, there is no objective scoring system that is clearly applicable to the pediatric population, though by subjective report, video (Video S1, Video S2), and clinical documentation, there was clear improvement of opisthotonus in these patients.
4. Conclusions
Despite the retrospective, small, and open-label design, our study provides evidence that BoNT injections into paraspinal muscles ameliorates childhood opisthotonus without serious adverse effects. This treatment should be added to the armamentaria of treatment options for this form of axial dystonia, particularly in cases refractory to oral medications. Of note, over half of the patients reviewed here are believed to have a genetic etiology for their opisthotonus.
5. Materials and Methods
Here, we describe seven patients who presented to our center for management of opisthotonus and were treated with BoNT injections. Patients were followed clinically and we discussed features, dosing regimen, and outcomes through a review of clinical documentation and laboratory and radiology reports.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6651/13/2/137/s1. Video S1: Patient 1 prior to botulinum neurotoxin injections and nine days following injections. Video S2: Patient 2 prior to botulinum neurotoxin injections and five days following injections.
Click here for additional data file.
Author Contributions
Conceptualization and methodology, M.H. and M.P.; writing—original draft preparation, M.H.; writing—review and editing, supervision, M.P. and J.J. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, no IRB was required for preparation of this case series, ethical guidelines were followed to assure patient privacy was maintained. Written consent from patient guardians was obtained prior to obtaining video and images for purposes of education within a medical peer reviewed journal.
Informed Consent Statement
Informed consent was obtained from all patient guardians and obtained prior to acquiring video and images.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available to maintain patient privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Illustrative photographs of opisthotonus of patient 4 prior to receiving treatment displaying characteristic axial extension of the trunk and neck.
toxins-13-00137-t002_Table 2 Table 2 Characteristics of patients undergoing treatment of opisthotonus.
Patient Sex Age Genetic vs. Acquired Etiology of Opisthotonus Weight (kg) History of Dystonic Storm
1 M 15 mo Acquired—Post-infectious 7.3 Yes
2 F 26 mo Genetic—Hypomyelinating leukodystrophy-14 8.5 Yes
3 M 8 yr Genetic—NBIA/PKAN 23.7 No
4 F 10 yr Acquired—Perinatal HIE 25.7 Yes
5 F 3 yr Genetic—presumed 14.7 No
6 M 26 mo Genetic—CASK-related disorder 12.2 No
7 F 13 yr Acquired—Tardive dystonia 34.4 No
M = male, F = female, NBIA = neurodegeneration with brain iron accumulation, PKAN = pantothenate kinase associated neurodegeneration, HIE = hypoxic-ischemic insult, CASK = calcium/calmodulin-dependent serine protein kinase gene.
toxins-13-00137-t003_Table 3 Table 3 Botulinum neurotoxin dosing regimens for patients with prominent opisthotonus.
Patient Paraspinal Dosing (Units) Other Muscles Injected Total Dose (Units) Latency (Days) Adverse Effects Duration of Benefit (Weeks) Outcome Repeat Injections Required Other Treatments 1
1 150 None 150 3 None 12 Complete resolution of opisthotonus during maximal effect Yes Baclofen, clonazepam, diazepam, lorazepam, clonidine
2 120 Splenius capitis 170 5 None 14 Complete resolution of opisthotonus during maximal effect Yes Clonazepam, midazolam, dexmedetomidine, baclofen
3 260 Triceps brachii, pectoralis major, gluteus maximus 400 14 None 14–16 Complete resolution of opisthotonus during maximal effect Yes Clonazepam, baclofen, tetrabenazine
4 300 Splenius capitis, sternocleidomastoid 430 6 None 12–16 Complete resolution of opisthotonus during maximal effect No 2 Clonazepam, lorazepam, diazepam, baclofen, carbidopa/levodopa, gabapentin, dexmedetomidine, morphine
5 160 Splenius capitis, gastrocnemeus, rectus femoris 300 7 None 10 Complete resolution of opisthotonus during maximal effect No 3 Clonazepam, baclofen, phenol injections
6 220 Splenius capitis 290 3 None 12–14 Complete resolution of opisthotonus during maximal effect with gradual wearing off, remaining dystonia not impairing No Clonazepam, baclofen
7 300 Splenius capitis, gastrocnemeus 650 5 Neck weakness 2 16 Complete resolution of opisthotonus during maximal effect Yes Clonazepam, lorazepam, diazepam, trihexyphenidyl, baclofen, haloperidol, tetrabenazine, guanfacine, clonidine, carbidopa/levodopa, propranolol, carbamazepine, topiramate, duloxetine, cyclobenzaprine, methocarbamol, morphine, ketamine
1 Includes treatments tried by previous providers/institutions. 2 Subsequent injections omitted splenius capitis with resolution of symptoms 3 Increased posturing after wearing off was managed with increased dose of oral clonazepam 3 and oral baclofen.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Oral | DrugAdministrationRoute | CC BY | 33673369 | 19,648,951 | 2021-02-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adrenal insufficiency'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arthralgia'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diabetes mellitus'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
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