diff --git "a/notes/Ghai-Essential-Pediatrics_12.txt" "b/notes/Ghai-Essential-Pediatrics_12.txt" new file mode 100644--- /dev/null +++ "b/notes/Ghai-Essential-Pediatrics_12.txt" @@ -0,0 +1,2141 @@ +- +- +- +l +- +- +- +l +- +- +- ++ +- +- +- ++ +- +- ++ +- +- +- +1 +- +- +- +- +1 +- +- +- +- +- +1 +- +- +- +1 +- +- +- +- +- +1 +- +1 +--•---1---1,---1---11---1-------- +----+--+---+--+---l--t----1--t---l--+---t--t-------+--+---+50 --1- 1---+--+----1-------+--t--�------t---l ----1---1--- +- +- +- +1 +- +- +- +- +- +- +---t-------+--+---+--+---+--+---1--;----1---;---1---+-----�40 +1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 B Age (yr) + +Figs 15.46A and B: Blood pressure levels for boys at 50th precentile for height. Chart depicting 90th (closed diamonds), 95th (open squares) and 99th + 5 mm (open triangles) percentile values for (A) systolic and (B) diastolic blood pressures, representing cut off values for the diagnosis of pre-hypertension, stage I and stage II hypertension, respectively, in boys (based on the Fourth US Task Force Report on Hypertension). With permission from Indian Pediatrics 2007;44: 103-21 +Disorders of Cardiovascular System - + + +Systolic blood pressure in girls + +-- � --� -----+---t--- - +1 +--1 -�-- --- +- +-- +- f- +---t---+----+-------t--+----11---+------+-------+--+-----t--+---+150 - ______ f-- - +- + + + + + + + + + + +-- ------ --- - ----- -- +- +-- --- +--'-so +I- - -·-- ---- +-- -1---1---------c-- -1---1---t--+----1---t----+---1 ++-- +-- +---- +-- +--- +-- +--- +-- - - +-1- 1- ------- - -- + +�-t---+-----+--t----1--+---t---+------+---+-----+--t----t--+----+80 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 +Age (yr) + +A -+- 90th percentile o- 95th percentile -- 99th percentile + 5 mm + +Diastolic blood pressure in girls + +----f- -- f---------- ---1---�- +__ +, +____ +---1---+---t---f---1- --- ---- --- +l---t------+--------+--t----t--t----t--+----11---+---t---+-------+ 110 +-------·------- + +t--+-------t--+---+------+-------t--+-------t--+-----------+ 100 -··- --�--- -- f- --- - --- --- ---,- +1 +-- +1 - +- - -�- -::� +- +1 + + +90 + +-i."'__-+---l --�---_-_-_+�__-_-_-_-1_-_-_-_-�r--------���--- t----------------�J +1 +- +- +_, +- +-- � 80 +-�::- +,- +---r- +- +b-;, +- ----,._�.. +-- +-� --= +i:V-:'��=- + +--::'r---t------!;.. =:;.-"i'--- ,,--t-------+--t-------+--t-------+ 70 +- +- +----- ----- ---- -- -- - +1---�-----1--+----· -- + + + +� � +E + + +------ -- ---1- +'----1---- +�-- 1---+---t---l----+--+----- --1----1---1----1---f----t---1---1- 50 +- +------1- +1---+---t---1- +I +- +- +- ++ +- +- +1 +- +- +- +1 +- +- +- +- +1 +- +- +- +, +1 +- +- +- +1 +- +- +- +- ++ +- +- +- +1 +- +- +- +- +- +- +- +�-t-------+------t--+---t--+---1--+---t---t------+---+----+ 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 +B Age (yr) + +Figs 15.47A and B: Blood pressure levels for girls at 50th precentile for height. Chart depicting 90th (closed diamonds), 95th (open squares) and 99th + 5 mm (open triangles) percentile values for (A) systolic and (B) diastolic blood pressures, representing cut off values for the diagnosis of pre-hypertension, stage I and stage II hypertension, respectively in girls (based on the Fourth US Task Force Report on Hypertension). With permission from Indian Pediatrics 2007,·44.-103-21 +..E_s_s_ e_ _t_ia_i_P_e_d_ia_t_r_ics__________________________________ _ +n +- + + + + + + + + + + + + + + + + + + + + +.. 1o +i + + +bladder width of approximately 40% of the arm circumference midway between the olecranon and the acrornion. The inflatable bladder should cover at least two thirds of the upper arm length and 80-100% of its circumference. +The cuff is inflated rapidly to occlude the brachia! artery in the cubital fossa (at least 20-30 mm Hg above expected SBP). The cuff is deflated slowly at the rate of 2-3 mm Hg per second while auscultating at the cubital fossa. Systolic blood pressure is indicated by the appearance ofKorotkoff sounds (phase I) and diastolic blood pressure by its complete disappearance (phase V). Environmental con­ cerns with regard to mercury has resulted in replacement of mercury with aneroid sphygmomanometers and oscillometric devices. +Oscillometric techniques are easy to use but are susceptible to artifacts and require calibration. Improve­ ment in technology has resulted in widespread use of oscillometric devices for measurement of blood pressure in infants and children. Ambulatory blood pressure monitoring is a procedure where the child wears a device that records blood pressure at regular intervals, through a 24 hr period while the child performs regular activities, including sleep. This method is used as additional evalua­ tion of hypertensive children in certain circumstances. + +C nical Features +l +i +Hypertension in children is usually asymptomatic unless blood pressures are high or sustained. Symptoms are common with secondary hypertension. Headache, dizziness, irritability, epistaxis, anorexia, visual changes and seizures may occur with significant elevations of blood pressure. Marked increases in blood pressure may also result in cardiac failure, pulmonary edema and renal dysfunction. Hypertensive encephalopathy usually pre­ sents with vomiting, high temperature, ataxia, stupor and seizures. Hypertensive crisis may present with decreased vision, symptoms of encephalopathy, cranial nerve palsies, cardiac failure and rapid worsening of renal function. Eye examination may reveal papilledema or retinal hemor­ rhages. Subclinical target organ injury may occur in asymptomatic children and include left ventricular hypertrophy, increased carotid intima media thickness, retinopathy and microalbuminuria. Children with secondary hypertension due to chronic renal causes may present with polyuria, polydipsia, pallor, weight loss and growth retardation. + +Evaluaton +i +Children and adolescents with confirmed hypertension need evaluation to identify potential causes, identification of co-morbidities and extend of target organ damage. All cases of hypertension require a detailed history and physical examination. The history should include sleep +history, treatment history, smoking and alcohol intake, + +drug abuse and family history (early cardiovascular diseases, hypertension, diabetes, dyslipidemia or renal diseases). The birth history and growth patterns are elicited. Examination should focus on identification of pallor, edema, syndromic facies, ambiguous or virilized genitalia, rickets, goiter, and skin changes (cafe au lait spots, neurofibromas, rash, striae). Examination of eyes should be done to look for proptosis, extraocular muscle palsies and fundal changes. A detailed cardiovascular examination should be done for asymmetry of peripheral pulses, upper and lower limb blood pressures, cardiomegaly, heart rate, cardiac rhythm abnormalities, murmurs and pulmonary edema. Abdominal examination may reveal hepatomegaly, abdominal mass or epigastric or renal bruit. +Laboratory evaluation includes estimation of blood levels of creatinine and electrolytes and urinalysis. Renal ultrasound may identify a mass, scarring, congenital anomalies or disparate renal size. The evaluation of comorbidities requires fasting lipid profile and glucose levels to identify dyslipidernias, metabolic syndrome and diabetes mellitus. Children with history of sleep­ disordered breathing may benefit from polysomnography. An echocardiogram is used to identify left ventricular hypertrophy and screen for coarctation of aorta. Investi­ gations like plasma renin and aldosterone, plasma/urine steroid levels and plasma/urine catecholamines may be required. Children with suspected renal or renovascular hypertension need to be investigated by radionuclide scintigraphy, Doppler studies or angiography. + +Treatment +The treatment of hypertension in children and adolescents has two components, i.e. therapeutic lifestyle interventions and pharmacotherapy. Weight reduction, increased physical activity and dietary interventions are the major therapeutic lifestyle interventions. Weight reduction in overweight children results in significant reductions of blood pressure. In addition, weight reduction also decreases other cardiovascular risk factors like dyslipi­ demia and insulin resistance. Current physical activity recommendations for children include 30 to 60 min per day or more of moderate intensity aerobic exercise plus limitation of sedentary activity to less than two hours per day. Children with hypertension may benefit from a dietary increase in fresh fruits and vegetables, fiber, non­ fat dairy, as well as a reduction in salt consumption. The recommendation for adequate sodium intake is 1.2 g per day for children 4 to 8 yr old and 1.5 g per day for older children. +Children with symptomatic essential hypertension, +secondary hypertension, diabetes associated hypertension, evidence of target-organ damage (left ventricular +hypertrophy), or failed non-pharmacologic interventions require pharmacologic therapy. Agents approved for management of hypertension include angiotensin +converting enzyme (ACE) inhibitors, angiotensin receptor +Disorders of Cardiovascular System - + + +blockers (ARB), beta blockers, calcium channel blockers and diuretics (Table 15.23). ACE inhibitors and calcium­ channel blockers are commonly used in children. ACE inhibitors or ARB are preferred in patients with diabetes or chronic kidney disease. +The goal of therapy for pediatric hypertension should be to reduce blood pressure below 95th percentile, except in the presence of chronic kidney disease, diabetes or target organ damage, when the goal is to reduce blood pressure to less than 90th percentile. Pharmacotherapy is done in a stepped-care approach and usually starts with a low dose of a single agent (step 1). If blood pressure control is not achieved, the dose is titrated every two weeks until blood pressure goals are achieved or the maximum dosage for the drug is reached (step 2). If adequate blood pressure control is not achieved with a single agent, a second agent with a complementary mechanism of action should be added and dose titrated until adequate control or dosage limit is reached (step 3). If adequate blood pressure control is not achieved with a + +two-drug regime, a third agent from a different drug class should be added as mentioned earlier (step 4). +In the case of hypertensive emergencies, the safest way is to lower blood pressure using an antihypertensive medication that is administered by continuous intravenous infusion in an intensive care unit, where the patient can be monitored appropriately. In general, the pressure should be reduced by up to 25% over the first 8 hr (10% in the first hour), followed by a further gradual reduction in blood pressure over the next 36-48 hr. Too rapid a reduction in blood pressure may lead to cerebral ischemia. Drug choices include labetalol, nicardipine and sodium nitroprusside of which nicardipine is the preferred drug in children due to its efficacy and safety (Table 15.24). Many patients in hypertensive crisis are volume depleted because of a combination of decreased oral intake and pressure natriuresis. Volume repletion in such conditions will help restore tissue perfusion and prevent a precipitous fall in BP that may occur with intravenous anti­ hypertensive therapy. + + +Table 15.23: Dosage of common antihypertensive medications for outpatient management Agents Dose; frequency Comments + +ACE inhibitors, angiotensin receptor blockers +Captopril 0.3-6 mg/kg/ day; tid Enalapril 0.1-0.6 mg/kg/day; qd or bid Lisinopril 0.06-0.6 mg/kg/ day; qd Ramipril 6 mg/m2; qd +Irbesartan 4-5 mg/kg/ day Losartan 0.7-1.4 mg/kg/day; qd +Calcium channel blockers + + +Use cautiously if GFR <30 ml/min/1.73 m2; avoid in renal artery stenosis +Use smaller doses in neonates +Monitor serum potassium, creatinine regularly Hyperkalemia, impaired renal functions; anemia, +neutropenia, dry cough infrequent + + + +Amlodepine Nifedipine (extended + +Isradipine Beta-blockers +Atenolol Metoprolol Labetalol + +Alpha agonists Clonidine Prazosin +Vasodilators +Hydralazine Minoxidil + +Diuretics +Frusemide Spironolactone* Metolazone +H ydrochlorothiazide Amiloride* + + +0.05-0.5 mg/kg/ day; qd-bid 0.25-3 mg/kg/day; qd-bid + +0.15-0.8 mg/kg/day; tid + +0.5-2 mg/kg/ day; qd or bid 1-6 mg/kg/day; bid +10-40 mg/kg/ day; bid or tid + + +5-25 µg/kg/ day; tid or qid 0.05-0.5 mg/kg/ day; bid or tid + + +1-8 mg/kg/ day; qid +0.1-1 mg/kg/day; qd or bid + + +0.5-6 mg/kg/ day; qd or bid 1-3 mg/kg/day; qd or bid 0.2-0.4 mg/kg/day; qd +1-3 mg/kg/day; qd +0.4-0.6 mg/kg/ day; qd + +Extended release nifedepine must be swallowed whole +Side effects: headache, flushing, dizziness, tachycardia; lower release) extremity edema , erythema + + +Decrease dose by 50% at GFR <50 ml/min/1.73 m2; give on alternate days at GFR <10 ml/min/1.73 m2; sleep disturbances with propranolol, metoprolol; hyperlipidemia; avoid in asthma, heart failure; blunt symptoms of hypoglycemia + +Abrupt cessation may cause rebound hypertension; sedation May cause 'first dose' hypotension, syncope + + +Hypertension refractory to other drugs; +Side effects: headache, palpitation, fluid retention, congestive heart failure; pericardia! effusions and hypertrichosis with minoxidil + + +Monitor electrolytes, fluid status periodically +Thiazides: dyslipidemia, hyperglycemia, hyperuricemia, hypokalemia, hypomagnesemia +Loop diuretics: metabolic alkalosis, hypokalemia, hypercalciuria *Use cautiously with ACEI, angiotensin receptor blockers + +qd once daily; bid twice daily; tid thrice daily; qid four times qd +__ ss_en_t____Pe_d___r_c_________________________________ _ +_ +i +s_ +i +at +i +ai +E +__ + +Table 15.24: Antihypertensive agents for management of severe hypertension +Medication Onset Duration of Route Dose Side effects effect + +Sodium 30sec nitroprusside + +Labetalol 5-10 min + + + +Nicardipine 1-10min + + + +Nitroglycerine 2-5min Phentoline lOmin + + +Nifedipine 10-30 min + +Clonidine 15-30 min + +<10min + + +3-6hr + + + +3hr + + + +5-10min 30-60 min + + +1-4hr + +2-4hr + + +IV infusion + + +IV infusion + +IV bolus + +IV infusion + +IV bolus + +IV infusion IV bolus + + +Oral + +Oral + + +0.5-8 µg/kg/min (made in 5% dextrose) + +0.25-3 mg/kg/hr + +0.2-1 mg/kg/dose q 5-10min (max 40mg) +0.5-4µg/kg/min (max 5mg/hr) +30 µg/kg (max 2 mg/ dose) q 15min +1-3 µg/kg/min +0.1-0.2 mg/kg (max 5mg) q 2-4hr if +required +0.2-0.S mg/kg (max 10mg) q 4to 6hr +0.05-0.1mg/dose, may repeat q hr; max 0.8 mg total dose + + +Nausea, vomiting, headache, tachycardia, cyanide toxicity (dizziness, confusion, seizures, jaw stiffness and lactic acidosis) Orthostatic hypotension, bradycardia, pallor, abdominal pain, diarrhea + + +Flushing, reflex tachycardia, phlebitis, nausea, increased intracranial pressure, headache + +Methemoglobinemia, headache, tachycardia Reflex tachycardia, abdominal pain + + +Excessive hypotension, peripheral edema + +Somnolence, dry mouth + + + + +Prevention +The prevention of high blood pressure in children can be achieved by preventing childhood obesity. Regular physical activity, consumption of fruits and vegetables, moderation of salt intake, low consumption of processed food items and animal fats and reducing sedentary activities will aid in reducing the prevalence of high blood pressure in children and adolescents. + +Suggested Reading +National High Blood Pressure Education Program Working Group on High Blood pressure in Children and Adolescents. The fourth re­ port on the diagnosis, evaluation and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114(2 Suppl 4th Report): 555-76 +Raj M, Sundaram KR, Paul M, Deepa AS, Kumar RK.,Obesity in chil­ dren - time trends and relationship with hypertension, Natl Med J In­ dia, 2007;20:288-93 + +PULMONARY ARTERIAL HYPERTENSION +Pulmonary arterial hypertension (PAH) is deined as resting +mean pulmonary arterial pressure greater than 25 mm Hg, or mean pulmonary artery pressure following exercise that exceeds 30 mm Hg. PAH occurs in an idiopathic form or in association with other etiologies. The condition is a critical determinant of morbidity and mortality in diverse pediatric cardiac, lung, hematologic, and other diseases. + +Etiology +PAH may be associated with a number of congenital heart diseases. Idiopathic PAH is rare in children. In a small + + +proportion mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, the activin receptor-like kinase type 1 (ACVRLl), or endoglin are identified. + +Persistent Pulmonary Hypertension of the Newborn (PPHN) +At birth, pulmonary vascular resistance is high, it normally falls rapidly throughout the first week of life. By 6 to 8 weeks, pulmonary vascular resistance usually has reached a normal adult level of 1 to 3 Wood units. These changes are accompanied by a gradual dilation of the smaller and then the larger muscular pulmonary arteries and develop­ ment of new arteries and arterioles. PPHN develops when pulmonary vascular resistance remains elevated after birth, resulting in right-to-left shunting of blood through fetal circulatory pathways. The common associations include congenital diaphragmatic hernia, meconium aspiration syndrome and perinatal asphyxia. These newborn patients typically require mechanical ventilatory support and those with underlying lung disease may benefit from high-frequency oscillatory ventilation or extracorporeal membrane oxygenation (ECMO). Pul­ monary vasodilators, such as inhaled nitric oxide, improve the outcome and reduce the need for ECMO. Sildenafil is increasingly used for PPHN as an alternative to inhaled nitric oxide. + +Clinical Manifestations +The clinical features of P AH are related to the degree of pulmonary hypertension and right ventricular function +Disorders of Cardiovascular System - + + +and status of the right ventricle. Most common symptom is exertional breathlessness due to the inability of the right ventricle to raise cardiac output with exercise. Other symptoms are hemoptysis, atypical chest pain, congestive heart failure, dizziness or syncope and arrhythmias. Cyanosis and its complications are seen in Eisenmenger patients but not otherwise unless there is a patent foramen ovale. A comprehensive evaluation is advised before a diagnosis of idiopathic PAH is made. It is essential to rule out cardiac (congenital heart disease), respiratory, upper airway obstruction (Down syndrome, adenoids), neurogenic causes (sleep apnea) and liver disease (porto­ pulmonary hypertension). + +Management +Supplemental low-flow oxygen alleviates arterial hypoxemia in patients with chronic pulmonary pare­ nchymal disease. Patients with Eisenmenger syndrome or idiopathic PAH do not exhibit resting alveolar hypoxia and do not require oxygen unless significantly hypoxic. Children with severe right ventricular failure and resting hypoxemia may require continuous oxygen therapy. +Diuretics are useful in patients with symptomatic right heart failure. The right ventricle is highly preload dependent, and care should be taken to avoid excessive diuresis since this can lead to a fall in cardiac output and compromise other pharmacologic measures, such as vasodilators. Patients are at higher risk of thromboembolic events due to sluggish pulmonary circulation and dilated right-sided cardiac chambers. Anticoagulants may have a role in select cases when the risk for thromboembolism outweighs the likelihood of hemoptysis. +The goal of vasodilator therapy for PAH is to reduce pulmonary artery pressure and increase cardiac output without causing systemic arterial hypotension. Sildenafil is an oral phosphodiesterase type 5 inhibitor that prevents the breakdown of cGMP and potentiates pulmonary vasodilation with inhaled nitric oxide. Symptomatic patients with PAH, PPHN and postoperative P AH benefit with sildenafil. Other agents including bosentan, an oral endothelin-receptor antagonist (ERA) and prostacyclin analogs. +Combined heart lung transplantation, or lung trans­ plantation alone has been performed successfully in patients with PAH. The major limitations to its widespread use include the limited number of centers with the expertise to perform the procedure and care for patients and the limited availability of suitable donors and signi­ ficant cost. + +Prognosis +Prognosis is dictated by the underlying etiology and the right ventricular function. An overall 80% 5 yr survival has been reported in patients with Eisenmenger syndrome compared with a 2-3 yr mean survival after the diagnosis of idiopathic PAH. + +Suggested Reading +Abman SH, Ivy DD. Recent progress in understanding pediatric pul­ monary hypertension. Curr Opin Pediatr 2011;23:298-304 +Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and as­ sessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:SSS-66 + +RHYTHM DISORDERS +The recognition of cardiac arrhythmias in children is challenging and requires a high index of suspicion. It is important to arrive at a precise diagnosis since the treatment is dictated by the specific arrhythmia. In some situations, it may be possible to affect a complete cure. + +Clinical Features +These are listed in Table 15.25. +Irregular heart rate. The commonest cause of an irregular heart rate is physiological sinus arrhythmia. This can be recognised by an increase in heart rate with inspiration and decrease with expiration. Sinus arrhythmia is usual following a febrile illness and by drugs that increase vagal tone (such as digoxin). It is readily abolished by exercise. Irregularities of rhythm are commonly seen in premature infants especially bradycardia associated with periodic apnoea. Common causes of heart rate irregularity in children include atrial and ventricular premature beats and conduction disturbances (Table 15.26). +Inappropriate heart rate. A heart rate that is inappropriately fast or slow for the clinical condition should arouse the suspicion of an underlying arrhythmia. Inappropriately + + +Table 15.25: Clinical features in arrhythmias +Irregular heartbeat +Heart rate that is inappropriate for the clinical condition Unexplained heart failure +Syncope, palpitations, chest discomfort +Underlying cardiac anomaly known to be associated with rhythm disorders +Family history of sudden cardiac events + +Table 15.26: Causes of irregular heart beat Sinus arrhythmia +Other common and usually benign causes +Supraventricular (atrial and junctional premature beats) Ventricular premature beats +Transient conduction disturbances (Wenckebach type), atrioventricular and sinoatrial blocks +Transient bradycardia in a premature infant +Uncommon but potentially serious causes +Mobitz type II heart block +Ectopic atrial tachycardia; multifocal atrial tachycardia Polymorphic ventricular tachycardia and Torsades Atrial fibrillation, with or without WPW syndrome Atrial flutter with variable conduction +_ E_s_en__t___Pe_d_ at_r_c_ _________________________________ _ +i +_ +s +_ +i +i +a +l +_ +s +_ + + + + + + + + + + + + + + + + + + + + + +. + + +I +l + + + + + + + + + + + + + + + + + + + + +10 + +slow heart rate in a child with fatigue, giddiness or syncope should arouse the suspicion of complete heart block. Inappropriately fast rates suggest tachyarrhythmias such as SVT. +Unexplained heart failure. Incessant arrhythmias such as ectopic atrial tachycardia (EAT), permanent junctional re-entrant tachycardia (PJRT) and some forms of ventricular tachycardia can present as heart failure. At the time of initial evaluation the heart rates may not be inappropriate for the degree of heart failure. Diagnosis may be missed and requires a high index of suspicion. These conditions should be considered in the differential diagnosis of childhood dilated cardiomyopathy, especially if the heart rate is relatively fixed. +Underlying conditions. A number of congenital and acquired heart diseases and certain systemic conditions are known to be associated with cardiac arrhythmias (Table 15.27). Ventricular and supraventricular arrythmias can follow cardiac surgery for correction of CHO. Operations resulting in scar formation in the right ventricle such as repair of tetralogy of Fallot are known to be associated with ventricular tachycardia. The Fontan operation for single ventricle physiology or the Senning or Mustard procedure for transposition is known to result in a particularly high incidence of re-entrant atrial arrhy­ thmias. Organophosphate exposure, tricyclic anti­ depressant overdose, digoxin toxicity, antiarrhynic drug treatment and substance abuse can be associated with a variety of arrhythmias. +Syncope. The commonest cause of syncope in children is mediated via the autonomic nervous system, known as + +Table 15.27: rrhythmias suggestive of specific congenital heart disease +Sick sinus syndrome +Sinus venosus, atrioventricular canal defect, Holt Oram syndrome with atrial septal defect (ASD) +Narrow QRS tachycardias +Ebstein anomaly; corrected transposition with Ebstein anomaly +Atrioventricular canal, ASD. pulmonic stenosis, total anomalous pulmonary venous connection, tricuspid atresia (older patients) +Atrial fibrillation and flutter +Congenital mitral stenosis, total anomalous pulmonary venous connection, coronary AV fistula +WPW and pre-excitation syndromes +Ebstein anomaly; corrected transposition with Ebstein anomaly +Wide QRS tachycardias +Anomalous left coronary artery from pulmonary artery, coronary AV fistula, arrhythmogenic rightventricle, atrio­ ventricular conduction defects, corrected transposition of great arteries; Ebstein anomaly +Postoperative patients +Supraventricular, ventricular arrhythmias + + +the neurocardiogenic syncope or vasovagal syncope. A fraction of syncopal episodes result from cardiac arrhythmias. Life threatening ventricular tachycardia (VT), as associated with long QT syndrome characteristically results in syncope. It is important to differentiate them from vasovagal episodes. Vasovagal syncope occurs in specific situations like prolonged standing in a hot environment, sight of blood, painful stimulus, emotional stress or following a recent illness. Syncope secondary to arrhythmia are sudden, unpredictable, paroxysmal and usually have no predisposing cause or premonition. Dura­ tion of syncope depends upon the duration of arrhythmia. Some forms of long QT syndromes and catecholemenergic tachycardia are precipitated by exercise. Ventricular tachycardia secondary to Brugada syndrome may be precipitated during febrile illness. +Palpitations and chest discomfort. Older children may complain of episodic palpitations. Not infrequently, they have a sensation of chest discomfort or pain during tachyarrhythmia . + +Basic Electrophysiology Concepts +Arrhythmia that originates at or above the bundle of His has narrow QRS morphology; that below this level (Purkinje fibers, ventricular muscles) have wide QRS morphology. Majority of tachycardia in children are regular. Common irregular tachycardia are ectopic atrial tachycardia, multifocal atrial tachycardia, atrial flutter with varying conduction, atrial fibrillation (rare in children) and ventricular fibrillation. During a regular narrow QRS tachycardia, if a P wave is identified and has normal morphology, axis and 1:1 P and QRS relation, it suggests sinus tachycardia. Absence of any of the three suggests supraventricular tachyarrhythmia. +Re-entrant vs. automatic tachyarrhythmias. Tachyarrhythmia is generally considered to result from one of the three mechanisms: re-en try, increased au tom a tici ty and triggered activity. In children, the first two mechanisms account for most important arrhythmias. Clinical and EKG features together with response to certain medications and maneuvres help distinguish re-entrant tachyarrhythmias from those due to increased automaticity. Re-entrant arrhythmias characteristically have a relatively sudden onset and termination. Successful termination with DC cardioversion or overdrive pacing (pacing at rates faster than the arrhythmia rate) strongly suggests a re-entrant mechanism. Automatic arrhythmias characteristically have a relatively slow onset. Gradual acceleration (warm­ up) to the peak rates may be demonstrable at onset and gradual deceleration (cool down) at termination is seen. + +Diagnostic Workup of Suspected Arrhythmia +Attempts should be made to answer all the questions listed in Table 15.28. This will allow the specific treatment strategy to be initiated. A 12 lead EKG should be obtained +Disorders of Cardiovascular System + + + +Table 15.28: Initial assessment of arrhythmia +Can the clinical condition result from a cardiac arrhythmia? Is there hemodynamic instability? +Is the arrhythmia incessant or episodic? +Is this a re-entrant arrhythmia or does it involve an automatic focus? +Where is the arrhythmic focus or circuit located? Is there an underlying structural heart disease? + + +and cardiac rhythm monitoring should be initiated as quickly as possible. + +Management of Hemodynamic Instability +All tachyarrhythmias and bradyarrhythmias influence hemodynamics adversely, manifesting with no detectable manifestations to circulatory collapse. Extreme hemodynamic instability is relatively rare in childhood arrhythmias, particularly in absence of structural heart disease. Hemodynamic instability necessitates emergency treatment. Most unstable tachyarrhythmias are broad QRS. Unstable narrow QRS tachycardia are quite uncom­ mon, especially in the absence of structural heart disease. Low energy (0.5-2 J /kg) synchronized DC cardioversion should be performed. If and when possible cardioversion should always be preceded by administration of a short­ acting benzodiazepine such as midazolam (0.1-0.2 mg/ kg/dose). Emergency treatment options for brady­ arrhythmias are shown in Table 15.29. + +Diagnosis and Management of Tachyarrhythmia +A combined strategy that simultaneously addresses both diagnosis and treatment is appropriate. This is determined by the QRS duration on the initial EKG and presence or absence of hemodynamic instability. Based on the QRS duration arrhythmias can be classified as narrow and wide. This is a useful practical classification and serves as an excellent guide to initial treatment. Age specific normal values for QRS duration are given in Table 15.30. As a preliminary step, sinus tachycardia should be excluded. Rates as high as 240/min can occasionally be recorded during sinus tachycardia. There is always an underlying cause for sinus tachycardia and this is usually apparent during the initial evaluation. Fever, circulatory failure, extreme dehydration, accidental ingestion of drugs and + +Table 15.30: Normal QRS duration at various age groups Age group QRS duration in seconds +0-6 months 0.03-0.07 (0.05) 1-5 yr 0.04-0.08 (0.06) 10-15 yr 0.04-0.09 (0.07) >15 yr 0.06-0.09 (0.08) +Values represent range (mean) + +toxic substances are common examples. Figure 15.48 depicts a useful treatment algorithm. +Narrow QRS tachycardia. Most narrow QRS tachycardias (Table 15.31) are reasonably well tolerated and allow a preliminary diagnostic workup (Table 15.32). If a patient is seen during an episode of tachyarrhythmia, all attempts should be made to obtain quality data before terminating the arrhythmia. Information that should be specifically sought include the P wave morphology and P-QRS relationship. P waves that appear normal during the tachy­ arrhythmia suggest sinus tachycardia. Ectopic atrial tachycardia is suggested by abnormal P wave morpho­ logy. Inverted P waves may be seen when atria are acti­ vated in a retrograde fashion as in the case of re-entrant tachyarrhythmias involving accessory pathways (AV re-entrant tachycardia) (Fig. 15.49). Often P waves are not + + + +Stable narrow QRS tachycardia Adenosine 140 µg/kg bolus +l l +Sudden Failure of the tachycardia to +.. +termination terminate after adenosine +.. +j t +AVNRT Sinus Flutter Ectopic atrial +• +! +AVRT tachycardia tachycardia ++ + +Treat the cause Cardioversion Beta blockade, ++ +dlgoxin, +Digoxin, amiodarone +beta blockade, +amiodarone + +fig. 15.48: Management algorithm for stable narrow ORS tachycardia. AVNRT atrioventricular no dal re-entrant tachycardia; AVRT atrioventricular re-entrant tachycardia + + + +Table 15.29: Emergency treatment for bradyarrhythmias +Modality Indication Dose + +Atropine Isoproterenol + +Transcutaneous pacing +Transvenous pacing + + +Severe sinus bradycardia, AV block with narrow QRS (supraventricular) escape 0.02 mg/kg IV bolus Lack of response to atropine, AV block with wide QRS (ventricular) escape 0.1-2 µg/kg/min +IV infusion Severe symptomatic bradycardia, asystole (not suitable for infants, young Twice the capture +children) threshold Alternative to transcutaneous pacing for infants and young children Twice the capture +threshold +_ E_sse_ _ tia_ _ _ed_ ia tric_ _________________________________ +s +i +P +n +_ +_ +_ +_ +_ +_ +_ +_ + +Table 15.31: Causes of narrow QRS tachycardia +Site Re-entrant arrhythmias Automatic arrhythmias +Sinus node Sinus node re-entry Sinus tachycardia +Atrium Intra atrial re-entrant Ectopic atrial +arrhythmias following tachycardia cardiac surgery Multifocal atrial (Fontan, Senning tachycardia operations) +Atrial flutter Atrial fibrillation +AV node AV node re-entry Junctional ectopic tachycardia +Accessory Atrioventricular pathway re-entry involving +concealed or manifest (WPW) pathway +Permanent junctional re-entrant tachycardia + + + + +clearly seen on baseline EKG but are unmasked by adenosine. Evidence of 2:1 AV conduction as suggested by a 2:1 P-QRS ratio during a narrow QRS tachycardia indicates atrial flutter (Fig. 15.50). Evidence of complete AV dissociation (no consistent P-QRS relationship) indicates junctional ectopic tachycardia. +Adenosine administration acts by producing a marked slowing of AV node conduction (Table 15.32). The effect of adenosine lasts for a few seconds. Side effects are short­ lived and include flushing, chest pain and dyspnea. + +Adenosine needs to be administered rapidly followed by rapid push of normal saline as a bolus. The recommended dose is 50-300 µg/kg. Most re-entrant tachycardias, where AV node is a part of the circuit (AV node re-entrant tachy­ cardia, AV re-entrant tachycardia) will be terminated by adenosine. Atrial flutter is seldom terminated by adenosine. The transient AV block that results from adenosine administration can unmask flutter waves on the EKG thereby confirming the diagnosis (Fig. 15.51). Similarly transient slowing of AV conduction can unmask ectopic atrial tachycardia. If adenosine is not available, vagal maneuvres can be attempted. For infants and young children an ice filled plastic bag placed on the face is the most effective vagal maneuver. Older children can be encouraged to perform the Valsalva maneuver or carotid sinus massage can be attempted. Eyeball pressure is contraindicated in infants. +Wide QRS tachycardia. Wide QRS complex tachycardias usually result from foci or circuits in the ventricles. Some supraventricular tachycardias can also result in a wide QRS configuration. The overall approach is quite similar to narrow QRS tachycardias, with identification of P waves, defining P-QRS relationship and determining the QRS axis configuration (Fig. 15.52). +Demonstrable AV dissociation (inconsistent P-QRS relation) suggests ventricular tachycardia (VT). In most situations, however, it is not easy to distinguish VT from SVT. If the patient is stable, administration of adenosine will terminate or unmask SVT. If there is no response, treatment for VT should be initiated. In stable patients it is better to initiate pharmacologic treatment of VT before considering cardioversion since the response to initial + + + +Table 15.32: Differential diagnosis of narrow QRS tachycardia + +Arrhythmia +Sinus tachycardia Sinus node-entry +Ectopic atrial tachycardia + + +Atrial flutter + +Postoperative intra atrial re-entry* + +Multifocal atrial tachycardia Junctional ectopic tachycardia + + +AV nodal tachycardia + +AV re-entrant tachycardia + +Junctional re-entrant tachycardia + + +P waves +Normal Normal +Abnormal and +different from baseline +Saw tooth appearance +rates exceed 240/min +Slow atrial flutter, P +waves different from baseline +Multiform +Normal (AV dissociation) or inverted (1:1 retrograde conduction) +Usually not visible (masked by RS complexes) +Inverted (retrograde VA conduction) +Inverted (long VA conduction time) + + +P-QRS relationship +1:1 +Usually 1:1 +Usually 1:1 + + +2:1 or 1:1 + +Variable, often 1:1 + + +Usually 1:1 Complete AV +dissociation is diagnostic +1:1 + +1:1 + +1:1 + + +Response to adenosine +Transient slowing; AV block No effect or transient AV block No effect or transient AV block + + +Transient AV block may unmask flutter waves; rarely arrhythmia terminates +Transient AV block may unmask flutter waves; rarely arrhythmia terminates + +No effect or transient AV block +No effect on rate; transient retrograde VA conduction block unmasks AV dissociation +Sudden termination is characteristic + +Sudden termination + +No effect or transient termination + + +*Postoperative intra atrial re-entry may follow surgery that results in atrial scarring, e.g. Fontan operation, Senning operation +Disorders of Cardiovascular System - + +--'-1,01• 11 •• •O n l +I +' +- I·I- ' II ·. - 1-: .s '' ,C -' ' +I +I +1 T +,I +_- +' +- +-ci +I- +. +:, +- +. +, +- +- +,� +� +- +- +' +-- +-- --·- . . �-___4�!·--i ·- C .f!- � -. . +- +- +f - +- +- +. +- +� +! +1 +f +.� !• 1 , •. I I I +i-l +- +I +I +I I I ., ' II I ,- I T, ,-,- +i +- +I +' +' +. +·11' : +·- +-; +- +=r � +. +� +I +I +I ++�-+ +I +I +I I �.J , I , I I I I I i I I I I . +I +r +-, +H- +il- +'-t�4- +1 +rhr, +rr ++- +f-f +-r +j +- l +i +- +: +1 +�@ +I +! +,-- +I. +>;---Tr· 1 lf 1,- f t- _, -1--'-l- --� � t'>--' I_l I 'I t • l TI l 4-,-t- ll t-- +; +J +tJ +I +l! +It; +Fig. 15.49: Six lead ECG. Adenosine was administered to a child with regular narrow ORS supraventricular tachycardia. Note the tachycardia terminates with a P wave. Note delta waves with short PR interval that is prominently seen in lead I. Adenosine administration was therapeutic in this case + + + + + + + + + + + + + + + + + + + + + +Fig. 15.50: Regular narrow ORS tachycardia at a heart rate of 150/min. Heart rate was fixed at 150/min for several hours that was suggestive of underlying arrhythmia. P waves were abnormally broad and tall + + + +treatment can help decides longterm therapy. Lignocaine is the initial choice, while procainamide is an effective alternative; others include amiodarone, sotalol, mexeletine +and flecanide. + + +Unstable wide QRS tachycardia. Wide QRS tachycardia with hemodynamic instability is a medical emergency. Synchronised cardioversion (0.5-2 J /kg) should be +performed immediately. For pulseless patients, CPR +_ E_s_s_e_n__ia r_P_e_d_ ia tr_ic_________________________________ I I I I I I I I I I +_ +s +t +_ +_ +_ +_ + + + + + + + +I I +.. ._ ' ll V (\ r• .. fl\ +L � +, + + + + + + + +Fig. 15.51: Response to adenosine administration to a child with atrial flutter. Note the unmasking of flutter waves that are prominently seen in lead II and Ill. Prate was 300/min. Before administration of adenosine, there was 2:1 AV conduction. The blocked Pwaves were hidden within the ORS complexes. After administration of adenosine, AV block increased and AV conduction block increased to 4:1 unmasking the flutter waves + + + + + +Intra-cardiac + + + +a a a a a a a +� +Intra-cardiac fn +Surface p p p + +Wide ORS tachycardia ++ + +Stable Unstable +! +If 1 :1 P-QRS relation, try adenosine DC shock ++ +If AV dissociation IV lignocaine +1 mg/kg or IV amiodarone 45 mg/kg +If no response, DC shock CPR + +CPR = Cardiopulmonary resuscitation +Fig. 15.53: Management of wide ORS tachycardia + + + +Fig. 15.52. Wide ORS tachycardia resulting from a re-entrant circuit involving an accessory pathway in a patient with right bundle branch block. Surface ECG, can be mistaken for ventricular tachycardia. ECG of the top two rows has been obtained directly from the atrium using postoperative atrial wires as electrodes. The bottom strip is the surface ECG from a monitoring lead. Conversion to sinus rhythm after adenosine is seen in the last four complexes on the right. a artial contraction, P p wave + +should be initiated. Subsequent treatment should follow standard guidelines recommended for pulseless patients with VT (Fig. 15.53). +Irregular wide QRS tachycardia. Sustained and irregular wide +QRS tachycardia is uncommon and usually suggests a diagnosis of Wolf Parkinson White (WPW) syndrome with atrial fibrillation. In presence of hemodynamic instability, synchronised cardioversion (1-2 J /kg) is indicated. If the patient is stable, procainamide infusion may be tried. + + +Once the arrhythmia has been managed, recurrences need to be prevented. Most childhood arrhythmias warrant evaluation by a pediatric cardiologist for followup care and to plan definitive treatment. An echocardiogram, Holter test (24 hr ambulatory EKG recording) and eso­ phageal electrophysiologic study is often required. Invasive intracardiac electrophysiologic study is com­ bined with radiofrequency (RF) ablation. Most accessory pathways are now treated by radiofrequency ablation, especially in older children (>4-yr-old). For younger children RF ablation is reserved for refractory situations. + +PREVENTING ADULT CARDIOVASCULAR DISEASE +Major risk factors for cardiovascular disease in adulthood include cigarette smoking, hypertension, dyslipidemia, diabetes mellitus, obesity and physical inactivity. Some of these risk factors have genesis in childhood and are +Disorders of Cardiovascular System + + +Table 15.33: Pediatric diseases with high cardiovascular risk in adulthood + +Category +Tier I (high risk) + + + + +Tier II (moderate risk) + + + +Tier III (at risk) + + +Diseases +Homozygous familial hypercholes­ terolemia (FH); diabetes mellitus type 1; chronic kidney disease; post heart transplantation; Kawasaki disease with current coronary aneurysms +Heterozygous FH; Kawasaki disease with regressed coronary aneurysms, diabetes mellitus type 2; chronic inflammatory disease +Post cancer-treatment survivors; congenital heart disease; Kawasaki disease without detected coronary involvement + +Prevention oriented targets +Maintain BM! <85th centile; blood pressure <90th centile; and LDL cholesterol (LDL-C) <100 mg/di + + + +Maintain BM! <90th centile; blood pressure <95th centile; and LDL-C <130 mg/di + + +Maintain BM! :;95th centile; blood pressure :;95th centile plus 5 mm Hg; and LDL-C :;160 mg/dl + +All tiers require maintaining fasting blood sugar <100 mg/ di and glycosylated hemoglobin (Hb Ale) <7%. + + + +amenable to modification, contributing to primary prevention of cardiovascular disease. + +Childhood Obesity +Obesity influences major cardiovascular risk factors such as dyslipidemia, hypertension, glucose intolerance and inflammation. Emerging cardiovascular risk factors like carotid intima media thickness as well as carotid elasticity has also shown strong association with childhood obesity. Childhood obesity is managed by a combination of increased physical activity and dietary interventions. + +Hypertension +Primary or essential hypertension is the most common form of hypertension in older children and adolescents. Childhood obesity is associated with hypertension in children, which often tracks into adulthood. + +Dyslipidemia +Screening for dyslipidemia is recommended for children whose parents and/ or grandparents required coronary artery bypass-surgery or balloon angioplasty before age 55, those with a family history of myocardial infarction, angina pectoris, peripheral or cerebral vascular disease, or sudden death before age 55 and those whose parents have dyslipidemia. Youth with dyslipidemia are treated with a diet low in total and saturated fats and cholesterol. The intake of complex carbohydrates is increased, whereas that of simple sugars is decreased. Drug therapy is used in patients with significantly elevated LDL-cholesterol. + +Diabetes Mellitus +Diabetes mellitus is associated with cardiovascular complications, which develop early in childhood and adolescence. Endothelial dysfunction seen in both types of diabetes is recognized to aggravate cardiovascular risk in later life. Optimal daily and longterm glycemic control, maintenance of blood pressure and lipid levels in the normal values for age, regular exercise, healthy diet and avoidance of smoking are necessary. + +Tobacco Consumption +Mechanisms by which smoking exerts its detrimental effects on cardiovascular system include endothelial dysfunction, increased oxidative stress, increased arterial stiffness, alterations in lipoprotein metabolism and induction of prothrombotic state. School based campaigns to prevent smoking and chewing tobacco are appropriate tools to contain this public health concern. Parents should be role models to children by avoiding or quitting smoking and chewing tobacco. +Early atherosclerotic disease has been documented in certain conditions in children. The risk category, group of diseases in each category and the prevention oriented treatment targets are shown Table 15.33. + +Suggested Reading +Raj M. Obesity and cardiovascular risk in children and adolescents. Indian J Endocrinol Metab 2012;16:13-19 +Raj M, Sundaram KR, Paul M, et al. Obesity in children -time trends and relationship with hypertension. Natl Med J India 2007; 20:288-93 + + +Disorders of +Urinary Tract + +Kidney and + + + + + +Arvind Bagga, Aditi Sinha, RN Srivastava + + + + + + + +RENAL ANATOMY AND PHYSIOLOGY +Each kidney is composed of approximately a million nephrons, each consisting of a glomerulus and renal tubule. The glomerulus is made of a tuft of capillaries and a central region of mesangium. The capillaries arise from the afferent arteriole and join to form the efferent arteriole, the entry and exit being at the hilum of the kidney. The capillary wall consists of fenestrated endothelium, glomerular basement membrane and foot processes (podocytes) of visceral epithelial cells. The basement membrane is made of type IV collagen, laminin and heparan sulfate proteoglycan. The Bowman space leads into the proximal tubule that has an initial convoluted portion, then the straight segment, descending and ascending limbs of the loop of Henle and the distal tubule. Six to eight distal tubules join to form the collecting ducts that finally enter the renal pelvis. +The renal artery divides into segmental arteries that branch to form interlobar and arcuate arteries. The latter give rise to the intralobar arteries, which provide the afferent arterioles for the glomeruli. The efferent arterioles from the glomeruli form a meshwork of peritubular venous capillaries that empty into intralobar veins. The early part of the distal tubule on its ascent from the medulla to the cortex lies near the glomerulus of the same nephron. The cells of the tubule in contact with the afferent arteriole are denser than the rest and called macula densa. The smooth muscle cells of the afferent arteriole, in this region, contain prominent cytoplasmic granules that are the site of renin activity. Thejuxtaglomerular apparatus CTGA) is composed of afferent and efferent arterioles, the macula densa and lacis cells located between these structures. The JGA is involved in systemic blood pressure regulation, electrolyte homeostasis and tubuloglomerular feedback. + +Renal Physiology +Glomerular filtration depends upon the higher pressure in afferent arterioles. The filtration barrier is constituted + +by the endothelium with slit pores, basement membrane and podocytes of visceral epithelial cells. Filtration of solutes depends upon their molecular size, shape and electrical charge. The filtrate from the glomerular capillaries passes from the Bowman capsule into the proximal convoluted tubule, loop of Henle, distal tubule and collecting ducts. The filtrate contains all the diffusible and ultrafiltrable substances present in plasma. Small quantities of protein are usually present, but are reabsorbed in proximal tubule. Bulk of the glomerular filtrate is reabsorbed into the peritubular capillaries and only 0.5% is excreted as urine. + +Tubular Reabsorption +The proximal tubules reabsorb about 80% of the glome­ rular filtrate. Approximately 65% of sodium is reabsorbed in the proximal tubule, through several active transport systems. Sodium transport is dependent on the parallel transport of bicarbonate, chloride, amino acids and glucose. Tubular reabsorption of sodium and other permeable solutes is promoted by the phenomenon of solvent drag during transport of water across the tubular epithelium. Figure 16.1 indicates the principal sites of reabsorption of sodium and potassium. +The glomerular filtration rate is regulated by tubulo­ glomerular feedback that depends upon the functional integrity of the JGA. Increased delivery of chloride to the macula densa results in local activation of renin-angio­ tensin mechanism. The renin-angiotensin-aldosterone system, prostaglandins and natriuretic peptides are involved in sodium handling. Potassium is completely reabsorbed in the proximal tubule; the amount seen in urine depends upon its secretion in the distal tubule. +Distal tubules and collecting ducts are responsible for urinary acidification, concentration and regulation of sodium balance. Exchange of potassium or hydrogen ions for sodium takes place in the distal tubules under the regulation of aldosterone. Antidiuretic hormone mediates + +464 +Disorders of Kidney and Urinary Tract + + + + + + + + +Proximal convoluted tubule +Na•(50%) +K• (65-70%) + + +Proximal straight tubule Na•(15%) + + + +Thin descending loop of Henle + + + + +Thick ascending loop of Henle + +Na•(20%) K•(20-25%) + + +Thin ascending loop of Henle +Na• (7%) + + +Cortical collecting duct + +Na•(2-3%) K•(2-5%) + + +Medullary collecting duct + + + + + + + +Fig. 16.1: Renal tubular handling of sodium and potassium. The major sites of reabsorption are shown, with percentage of filtered cation in parenthesis + + +absorption of water through insertion of 'water channels' (aquaporins) on the luminal surface of cells in the collecting tubules. +Renal acidification. The kidney helps in regulation of acid­ base balance by maintaining plasma bicarbonate concen­ tration at 24-26 mEq/1. Depending on dietary protein intake, children produce about 1-3 mEq/kg/day of nonvolatile acids. Filtered bicarbonate is almost completely reabsorbed, 85 to 90% in the proximal tubules and the rest in distal tubules and collecting ducts. Bicarbonate, consumed in the buffering of nonvolatile acids, is regenerated by the renal excretion of titrable acid and ammonia. Chronic acidosis augments the production of ammonia and thus elimination of acid. Figures 16.2 and 16.3 demonstrate the chief mechanisms involved in the reabsorption of bicarbonate and excretion of protons in the proximal and distal tubules, respectively. The reabsorption of filtered bicarbonate as well as excretion of acid is mediated by tubular secretion of hydrogen ions (H+). +In the proximal tubule, filtered HC03 combines with +H+ to form H2C03 that rapidly dissociates to H20 and CO2 +(catalyzed by carbonic anhydrase at the brush border of +the tubular basement membrane) (Fig. 16.2). CO2 diffuses +along its concentration gradient into the tubular cell, +combining with HP to generate HC03 that is absorbed +by the peritubular capillaries. The proximal tubule +reabsorbs 80-90% of the filtered HC03; the remainder is +reabsorbed distally. In the distal tubule, the secreted H+ ions combine with the major urinary buffers, sodium hydrogen phosphate (Na2HP04) and ammonia (NH3) to + +form NaH2P04 and NH/ (measured in urine as titratable +acidity and ammonium ion respectively) (Fig. 16.3). The distal nephron generates and maintains a steep pH gradient between the blood and urine, but its capacity to secrete H+ ions is small. Thus, even a slight increase in +distal HC03 delivery results in increase in urine pH. +Extracellular fluid volume and potassium balance also regulate H+ secretion and HC03 reabsorption. +Suggested Reading +Bernstein PL, Ellison DH. Diuretics and salt transport along the neph­ ron. Semin Nephrol 2011;31:475--82 +Srivastava RN, Bagga A. Renal anatomy and physiology. In: Pedi­ atric Nephrology, 5th edn. Jaypee, New Delhi, 2011;1-19 + +Development of Structure and Function +Differentiation of the primitive kidney is stimulated by penetration of the metanephros, during the fifth week of gestation, by the ureteric bud, which is an outgrowth of the lower portion of the mesonephric duct. Division of the ureteric bud within the metanephros induces the development of nephrons. The ureteric bud gives rise to the intrarenal collecting system, renal calyces, pelvis and ureter. The most active period of nephrogenesis is from 20--36 weeks. The full number of nephrons is present around 36 weeks. Partitioning of the cloaca during the 5th week results in the formation of the urogenital sinus anteriorly and the anal canal posteriorly. The upper part of the urogenital sinus differentiates to form the fetal bladder. +The fetal kidneys are lobulated structures that ascend from the pelvis to their normal position between 6 and +__ E_s_s_e_n_ ti_i_P_e_d_i_atric_________________________________ +_ +s +a +_ +_ +_ +_ +r + +Tubular lumen + + + + + +"T"·[ +Cabonic I +anhydrase+ + +Proximal tubular epithelial cell + + +--------------T 3 Na• +-� +I I I I +"] +W+OW I +I +I I +I +I +H• I �--+ +I Carbonic +anhydrase +I +L- - - - - -� Hco- +3 +1 I +_______ J + + +Interstitial fluid + + + + + +2 K• + + +Na• er +Voltage +1 mV Voltage -70 mV Voltage O mV +Fig. 16.2: Reabsorption of bicarbonate in the proximal tubule. Protons CH+) are secreted into the lumen through the actions of the sodium +(Na+) H+ antiporter (1) and the H+ ATPase (2). Secreted H+ combines with HC03 to form H2C03, which, under the action of Juminal membrane +carbonic anhydrase dissociates to H20 and CO2. The CO2 travels across the membrane into the cell where it combines with OH- to generate +HC03. The HC03 and Na+ cross the basolateral membrane using the Na+/HC03 symporter (3). Na+ also exits the cell via the Na+/K+ ATPase (4). Electrogenic H+ secretion generates a small lumen positive voltage, which creates current flow across the paracellular pathway + + +I - 10,�· + + +Tubular lumen + + + + + + + + + + + + +A + +Voltage +10 mV + + +Intercalated cell + + + + +Carbonic anhydrase + + + + + + + + + +Voltage -30 mV + +Interstitial fluid + + + + + + + + + + + + + + +Voltage OmV + + +Tubular Principal cell Interstitial lumen fluid +ENaC r� Aldostero +ne +Y +O + + +3 Na• Na• +=+ +�MR 2 K• receptor +K• +-r + + + + +BCl1-K• + +Voltage Voltage Voltage -10 mV -80 mV OmV + + +Figs 16,3A and B Mechanism of acidification and potassium excretion in the distal renal tubules. (A) The intercalated cells of the cortical collecting ducts secrete H+ through the H+ ATPase (1) and H+/K• ATPase (2), independent of Na• transport. The hydroxyl (OH-) ions generated +in the cell through H+ secretion exit the cell by the HC03/0- exchanger (3). The secreted H+ is buffered by luminal ammonia forming NH4 and +phosphate (titrable acids), to prevent a drop in luminal pH that would prevent further H+ secretion. (B) Principal cells mediate sodium (Na•) absorption and potassium (K·) transport. The apical membrane contains an amiloride sensitive Na+ channel (epithelial sodium channel, ENaC); Na• exits basolaterally via Na•/K+ ATPase (4 ). Sodium transport creates a lumen negative transepithelial potential that increases the rate of H+ secretion by intercalated cells. Aldosterone binds to the mineralocorticoid (MR) receptor and enhances Na• absorption and H+ and K+ secretion + + +9 weeks of gestation. These kidneys can be visualized on antenatal ultrasound by 12-13th week. The kidneys grow steadily in size between the 12th week and the 40th week, with the renal length increasing from about 1.0 cm to 2.7 cm. The fetal bladder is visualized by the 10-14th week, and its capacity increases steadily to about 50 ml at term. + +Beyond the 16th week, the amniotic volume is principally dependent on urine production. + +Glomerular Filtration +Glomerular filtration begins at 5-9 weeks' gestation, initiating urine formation. The fetal kidney receives about +Disorders of Kidney and Urinary Tract + + + +2-4% of cardiac output, which increases in neonates to 15-18%. Serum creatinine level is high at birth, reflecting maternal values, but falls rapidly to 0.3-0.5 mg/dl by the end of first week. Most (92%) neonates pass urine within the first 48 hr. The GFR is low at birth (15-20 ml/min/ 1.73 m2 in the first 3 days in term, 10-15 ml/min/1.73 m2 in preterm) but increases to 35--45 ml/min/1.73 m2 at 2 weeks and 75-80 ml/min/1.73 m2 by 2 months. + +Tubular Function +Tubular function contributes to urine formation around 14 weeks' gestation. Postnatal tubular maturation follows a pattern similar to GFR but its maturation is delayed. Infants have reduced sodium and bicarbonate reabsorption and limited ability for hydrogen ion excretion. The pH of urine in newborns is inappropriately high for the degree of acidemia. + +Plasma Osmolality +The capacity of the kidneys to concentrate or dilute urine is limited in neonates. An infant can concentrate his urine to a maximum of 700-800 mOsm/kg whereas the older child can achieve 1200-1400 mOsm/kg. Growing babies utilize most of the protein available for growth rather than catabolize to urea. Decreased production and excretion +of urea result in a relatively hyposmolar interstitium and +reduced urinary concentration. The newborn can dilute urine to a minimum of 50 mOsm/kg, like an older child. However, the time taken to excrete a water load is longer. Thus, delayed feeding and overdiluted or concentrated feeds are potentially harmful. + +Maturation of Renal Function +Renal function continues to improve during the first two years of life, at the end of which, various parameters of renal function approach adult values, if corrected to standard surface area. Structural growth parallels the functional maturation. + +Suggested Reading +De Curtis M, Rigo J. Nutrition and kidney in preterm infant. J Matern Fetal Neonatal Med 2012;25 51:55-9 +Quigley R. Developmental changes in renal function. Curr Opin Pediatr 2012;24:184-90 +Srivastava RN, Bagga A. Diseases of the newborn. In: Pediatric Neph­ rology, 5th edn. Jaypee, New Delhi, 2011;494-524 + +DIAGNOSTIC EVALUATION +Common manifestations of renal disorders include edema, hematuria, oligoanuria, dysuria and abnormalities of micturition, flank pain and ureteric colic. Serious renal disease may be present with subtle or no symptoms. With improvements in techniques and widespread availability of antenatal ultrasonography, several congenital anoma­ lies of kidney and urinary tract (CAKUT) are detected. Appropriate imaging procedures are needed to confirm + + +and define their severity. Abnormal urinary stream or dribbling of urine suggests an anomaly of the distal urinary tract. The causes of acute kidney injury in the newborn are different from those in older children. +During infancy, unexplained fever may be the only feature of urinary tract infection (UTI). UTI may be suggested by other nonspecific symptoms such as failure to thrive, diarrhea and vomiting. It is important to diag­ nose these infections since urinary tract anomalies may be present. An abdominal mass at this age is likely to be Wilms' tumor, hydronephrosis or multicystic renal dysplasia. An important cause of acute kidney injury, at this age, is hemolytic uremic syndrome. About 20% patients with minimal change nephrotic syndrome have onset of the disease between 2 and 3 yr. Renal tubular disorders such as renal tubular acidosis and Fanconi syn­ drome are usually diagnosed at this age. +Acute poststreptococcal glomerulonephritis (GN), rare below the age of 3 yr, is usual in older children. Rickets at this age is rarely due to vitamin D deficiency, unless there is malabsorption or chronic liver disease. Nephrotic syndrome beginning in adolescence may be of the non­ minimal type. Acute-on-chronic renal failure, previously +undetected chronic renal failure, symptomatic hypertension +and collagen vascular diseases are common. + +Clinical Features of Renal Disease Hematuria +Gross hematuria in acute GN is typically smoky brown or cola colored. Bright red blood suggests a nonglomerular cause, as in renal or vesical calculi. Gross hematuria is rare in UTI. Other conditions, which might impart a red color to urine include hemoglobinuria, myoglobinuria, porphyria and ingestion of beetroot. + +Edema +Acute GN presents with facial puffiness and gross hematuria; the edema does not pit readily on pressure. If fluid intake is not restricted, the edema may increase and involve hands, feet and legs. In nephrotic syndrome, edema develops insidiously, starting with eyelid puffiness most noticeable in the morning. Over a period of several days, there is pitting edema over the feet and legs. Facial swelling is often mistaken for allergy or insect bite. + +Oliguria +Oliguria, defined as urine volume less than 0.5 ml/kg per hr, commonly results from gastroenteritis and hypo­ volemia. Oliguria is an important feature of moderate or severe acute GN, acute tubular necrosis and conditions causing severe glomerular injury (e.g. HUS, vasculitis). + +Abnormalities of Micturition +A poor urinary stream in boys, especially in presence of a full bladder, suggests obstruction, most commonly due +_ E_sse_ n_ t_ i_ al_ P_ _ed_ _ ia_ tric_ _________________________________ +s +_ +_ +_ +_ + + +to posterior urethral valves. Persistent dribbling indicates abnormal ureteric insertion distal to bladder neck. Infants with meningomyelocele should be evaluated for bladder dysfunction. Dysuria, flank pain or ureteric colic suggest UTI or urinary tract calculi. + +Polyuria, Polydipsia +Impaired urinary concentration is a feature of obstructive uropathy and primary or secondary tubulointerstitial disorders. Polyuria is also present in conditions associated with deficiency or resistance to antidiuretic hormone, +diabetes mellitus, hypokalemia (e.g. distal renal tubular +acidosis) and hypercalcemia. +Enuresis +Primary monosymptomatic enuresis needs to be distin­ guished from patients with dysfunctional voiding. Most children with nocrnal enuresis have no evidence of renal disease. Urinalysis and culture are recommended in patients with secondary enuresis. +Hypertension +Assessment of blood pressure is necessary in all children, and especially those with disorders of the kidneys or urinary tract. Symptomatic hypertension is chiefly due to a renal parenchymal or renovascular cause; endocrine conditions are uncommon. + +Growth Retardation, Anemia +Physical retardation is a feature of chronic kidney disease (stage 3-5) and tubular disorders. Normocytic normo­ chromic anemia is striking in patients with chronic kidney disease (stage 3-5). Patients with unexplained anemia should be evaluated for a renal disease. + +Abdominal Mass +Multicystic renal dysplasia, polycystic kidneys, renal vein thrombosis, hydronephrosis (due to pelviureteric or lower urinary tract obstruction) and Wilms' tumor may result in palpable masses. + +Examination of Urine +Urinalysis is an important step for diagnosis of renal disease. Evaluation includes microscopic examination of the uncentrifuged as well as centrifuged specimen and semiquantitative or quantitative detection of different substances. + +Collection of Specimen +The first morning specimen is preferred since it is relatively concentrated. While a clean container is sufficient, specimens for culture should be collected in a sterile container. After cleaning the perineum with soap and water, a 'clean catch' sample is collected. If facilities for immediate processing are not available, the specimen is stored at 4°C for 12-14 hr. + + +It is difficult to obtain satisfactory specimens in children below 2-yr-old. Urine may be collected using a sterile bag that is applied after local cleaning and removed soon after the void. These specimens should not be used for culture. Other reliable ways for obtaining urine specimens in infants include percutaneous suprapubic aspiration or transurethral catheterization. + +Specific Gravity +Specific gravity is measured using either refractometer or hydrometer; the former is convenient, requires less volume of urine and gives accurate values. The early morning urine specific gravity should exceed 1015. + +pH +Urine is collected in a capped syringe if pH can be measured promptly. If measurement is likely to be delayed, urine should be collected under paraffin. Urine pH is lowest in the fasting, early moing specimen and increases following meals. + +Protein +Proteinuria is an important marker of renal injury. Detec­ tion of 3-4+ albuminuria suggests glomerular disease. Low molecular weight proteinuria, including lysozyme, �2 microglobulin, neutrophil gelatinase associated lipocalin and retinol binding protein, suggest tubular injury. Dipstick methods (Uristix) for proteinuria are convenient and reliable. Composite strips for pH, glucose, hematuria, leukocyte esterase and nitrite are also available. Proteinuria can also be semiquantitatively tested using the boiling and the sulfosalicylic acid tests. + +Reducing Substances +Reducing substances can be estimated by Benedict test or dipsticks based on the glucose oxidase method, both of which produce a graded color change. + +Microscopic Examination +A fresh, well-mixed specimen is examined for cellular elements, crystals and casts. Alternatively, urine is centrifuged at 1500 rpm for 10 min; urine is decanted and the cell pellet resuspended in 0.3-0.5 ml urine. Evaluation for hematuria, defined as more than 5 red cells/hpf in a centrifuged specimen is abnormal. Red cell casts indicate glomerular inflammation. Leukocytes may occasionally be absent despite significant bacteriuria. On the other hand, isolated presence of leukocytes is not specific for UTI, and may be noted in interstitial nephritis, stones and high fever. The detection of bacteriuria in fresh, uncentrifuged urine is significant. Figure 16.4 shows common abnormalities picked up on urine microscopic examination. +Disorders of Kidney and Urinary Tract + + + + + + + + + +A + + + + + + + + + +C +Figs 16.4A to D: Appearance of casts on urine microscopic examination. (A) White blood cell casts; (B) red blood cells casts, (C) hyaline cast; (D) Granular cast + + +Blood Tests +Blood levels of creatinine and urea are used to assess renal function. The normal levels of serum creatinine are 0.2-0.5 mg/ dl in children below 6 yr and 0.4-0.8 mg/ dl in older children. Blood urea ranges between 20-35 mg/dl during childhood. However, it is important to realize the limitations of these investigations. Normal values of blood urea or creatinine do not increase even when glomerular filtration rate is reduced by 50%. The level of serum creatinine is dependent on muscle mass and is, therefore lowinmalnutrition. Bilirubinmayinterferewithcreatnine measurements. Blood urea levels are low on a protein deficient diet and high with tissue breakdown, trauma, gastrointestinal bleeding and use of corticosteroids. Estimation of blood levels of cystatin C, which does not depend on the nutritional status, is considered a sensitive indicator of glomerular function. +Other specific investigations include albumin, choles­ terol, antistreptococcal antibody titers, complement, rnunoglobulins and autoantibodies. Estimation of blood pH, bicarbonate, electrolytes and osmolality are important in patients with tubular disorders and/ or renal failure. + +Glomerular Filtration Rate (GFR) +While clearance of inulin is regarded as the reference for estimating GFR, the test involves its accurate IV infusion followed by measurement of levels in timed urine and blood samples. Measurement of the creatinine clearance is adequate for assessing GFR in most cases. + +Creatinine Clearance +Creatinine clearance depends on the body size; the values are normalized to surface area. The normal creatinine + +clearance is 80-120 ml/minute per 1.73 m2• GFR can be estimated from serum creatinine (mg/ dl) and patient height (cm). The value of the constant k ranges between 0.41-0.43. + +Serum creatinine +GFR +ute per 7 +1. 3 +m +min _ +(ml/ 2) = __k_x_h_e�ig�h t +_ +Radionuclide Clearance +Disappearance curves of the radionuclides, 1251-iothala­ mate, 99mTc-DTPA or51Cr-EDTA following its IV injection can be used to accurately compute GFR. + +Tests of Tubular Function +Table 16.1 lists some important evaluations useful in diagnosing disorders of tubular function. + +Water Deprivation Test +Following a few hours of fluid deprivation, desino-8-0-arginine vasopressin (ODA VP) is administered nasally (5-10 µg neonates and infants, 20 µg children) or by IM injection (0.4-1.0 µg infants and young children, 2 µgolder children). Urine is collected every hr for the next 2-3 hr. Following administration of DOA VP, patients with nephrogenic diabetes insipidus fail to show a rise of urine osmolality that remains below 300 mOsm/kg (normal >800 mOsm/kg). Those with deficiency of the antidiuretic hormone concentrate urine appropriately following DOAVP administration. + +Imaging of the Urinary Tract Plain X-Ray +A plain film of abdomen provides information on renal size, shape and outline and radiopaque calculi. The length +___ _s_s_e_n_ t_ia_l_P_e_d_i_a _tr_c_ _________________________________ +i +s +E + + + + + + + + + + + + + + + + + + + + + + + + +- +i 1� + + +Table 16.1: Investigations for evaluation of suspected tubular diseases +Substrate Test +Phosphate Blood parathormone +Tubular reabsorption of phosphate Tubular maximum for reabsorption/GFR +Glucose Renal threshold and tubular maximum for glucose reabsorption +Amino acids Clearance of amino acid Bicarbonate Blood anion gap +Fractional excretion of bicarbonate H+ Minimum urinary pH +Urine anion gap; urine osmolal gap +U-B CO2 gradient +Water Maximum urine osmolality Water deprivation test Plasma ADH +Sodium Urinary sodium excretion Plasma renin, aldosterone +ADH antidiuretic hormone; GFR glomerular filtration rate + +of normal kidney approximates the height of first four lumbar vertebrae. A small kidney may indicate hypoplasia or chronic damage. The opposite kidney, unless diseased, shows compensatory hypertrophy. + +Ultrasonography +Ultrasonography is the initial modality for imaging kidneys and urinary tract in renal diseases. This investi­ gation is readily available, noninvasive and performed even in uncooperative patients, infants and those with renal failure. Anatomic details of the kidneys, ureters and bladder are examined. Doppler ultrasonography is useful for studying renal blood flow. + +Intravenous Pyelogram (/VP) +The patient is prepared as for plain X-ray. The radio­ contrast is injected and films taken at 2, 5, 10 and 30 min. IVP provides satisfactory details on renal size, shape, cortical outlines and calyceal pattern. The use of IVP has declined following the availability of radionuclide imaging. + +Micturating Cystourethrogram (MCU) +MCU is necessary for studying the lower urinary tract. A sterile catheter is introduced into the bladder, which is filled with contrast medium; films are taken during and end-micturition. MCU provides precise details of the anatomy of the bladder and urethra, presence of vesicoureteric reflux and obstruction in the lower urinary tract (e.g. posterior urethral valves, urethral stenosis). + +Radionuclide Imaging +Imaging of the kidney and urinary tract has been simplified by radionuclide methods, which have replaced conventional radiocontrast studies. Radionuclide + +procedures are noninvasive, highly sensitive and expose patients to less radiation compared to radiocontrast studies. The compounds, labeled with radioactive 99mtechnetium, commonly used include dirnercaptosuccinic acid (DMSA), diethylenetriaminepentaacetic acid (DTP A) and mercapto­ triacylglycine (MAG-3). Following IV injection, DMSA attains high concentration in the renal cortex and provides very high quality images of renal morphology. This is useful in detection and followup of renal parenchymal defects associated with urinary tract infections (Fig. 16.SA). DTPA is freely filtered by the glomeruli with no tubular reabsorption or excretion. A DTP A renogram is useful for evaluating perfusion and function of each kidney. +Obstruction to the urine flow can be diagnosed by study­ ing the effect of IV frusemide. Normally there is prompt washout of the radionuclide, but this clearing may not occur in subjects with upper urinary tract obstruction (Fig. 16.58). Renal arterial narrowing results in reduced renal blood flow and an abnormal pattern on DTPA renogram. This effect is accentuated by administration of angiotensin converting enzyme inhibitors, thus increasing its sensitivity in diagnosis of renal artery stenosis. MAG-3 provides highly satisfactory information on renal structure and function. +99mTc-labeled radionuclide scan can be used instead of the radiocontrast MCU. Radionuclide cystography is sensitive for detecting vesicoureteric reflux with minimal radiation exposure. However, this procedure does not provide sufficient anatomic details of bladder and urethra to recommend its use for initial evaluation of patients with suspected urinary tract obstruction, nor grading of vesicoureteric reflux. + +SuggestedReading +de Bruyn R, Marks SD. Postnatal investigation of fetal renal dis­ ease. Semin Fetal Neonatal Med 2008;13:133-41 +Gupta AK, Jana M. Imaging of the urinary tract. In: Pediatric Neph­ rology, 5th edn. Eds. Srivastava RN, Bagga A. Jaypee, New Delhi, 2011; 48-65 +Schwartz GJ, Munoz A, Michael F, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009;20:629-37 +Simoneaux SF, Greenbaum LA. Diagnostic imaging. In: Pediatric Nephrology, 6th edn. Avner ED, Harmon WE, Niaudet P. Lippincott Williams and Wilkins, Philadelphia 2009; 535-64 + +HEMATURIA +The presence of blood in urine imparts it a color, which includes various shades of deep red, smoky brown, cola­ color and faint pink. Parents may mistake very concen­ trated urine for that containing blood. Microscopic examination of urine will show red blood cells. Reagent coated dipsticks detect free hemoglobin and myoglobin. Red urine may be present in porphyria and following beetroot ingestion. Urine appears orange-colored after administration of rifampicin or pyridium. Uric acid crystals may also impart a pink tinge to the nappy. +Disorders of Kidney and Urinary Tract -- + + + +L R + + + + + + + + + + + + +A +Time in minutes +Figs 16.SA and B: (A) 99mTc-DMSA scintigraphy showing multiple scars and loss of volume in the right kidney. The left kidney is normal; (B) renal dynamic scan with diuretic was performed in a 6-wk-old newborn with isolated left hydronephrosis. The excretion of the tracer on the left side is sluggish and unchanged with administration of diuretic, suggesting an obstructive pattern of excretion, as seen with pelviureteric junction obstruction + + +In children, the commonest cause of gross hematuria is postinfectious GN. Urinary tract stones are not infrequent (Table 16.2). Gross hematuria is rare in acute pyelo­ nephritis. Conditions that cause persistent microscopic hematuria include idiopathic hypercalciuria, benign familial hematuria, Alport syndrome, IgA nephropathy and membranoproliferative GN. + +Diagnostic Evaluation +A history of pain in the flank or suprapubic region, dysuria and edema should be obtained. Physical examination includes assessment of growth and features of acute or chronic kidney disease such as edema, hypertension, unexplained pallor, bony abnormalities and abdominal mass. An audiogram and a detailed eye examination may be needed. Figure 16.6 shows an algorithm for evaluation of patients with hematuria. +A fresh specimen is examined for red cells, red cell casts and protein. Absence of large number of red cells in bloody urine suggests hemoglobinuria (intravascular hemolysis) + +or myoglobinuria. In glomerular disease, urine shows dysmorphic red cells, of different shapes, whereas in bleeding from renal pelvis or the lower urinary tract, the red cells maintain normal morphology (Fig. 16.7 and Table 16.3). Presence of significant proteinuria (2+ or more) and/or red cell casts suggests glomerular disease. Hypercalciuria should be excluded by determination of urinary calcium to creatinine ratio on one or more random samples. +A plain X-ray film of the abdomen and abdominal ultrasound is done to exclude major renal and urinary tract anomalies and calculi. Blood levels of creatinine are measured; other specialized blood tests depend on the likely clinical etiology. Surgical conditions that cause hematuria can be diagnosed by appropriate imaging. Invasive procedures such as cystoscopy are rarely indicated. +In a significant proportion, mild microscopic hematuria spontaneously disappears over a period of several years. Other family members may have similar urinary abnormalities. If there is no family history, a renal biopsy + + +Table 16.2: Causes of hematuria + +Glomerular +Postinfectious glomerulonephritis (GN) IgA nephropathy +Henoch-Schonlein nephritis Membranoproliferative GN Rapidly progressive GN + + +Uncommon Lupus nephritis +Other vasculitides, e.g. microscopic polyangiitis Membranous nephropathy +Familial benign hematuria Alpert syndrome + +Non-glomerular +Hypercalciuria Renal calculi +Urinary tract infection Hemorrhagic cystitis Trauma, exercise Cystic renal disease Interstitial nephritis +Uncommon +Vascular malformations Coagulation disorders Thrombocytopenia Nutcracker syndrome +Renal or bladder malignancy +__ _s_s_ _n_t_ial_P_ed_ia _r_ics ________________________________ +_ +t +E +e +_ +_ +_ +_ + + +Red urine +rinUrine dipstick, lmicroscopy field _.rNo + +I +-- +aly +s +__ +R +_ +B c +__ +h +igh +_ +po +is > S w +_ +er +_ +.__ +u +_ +, +_ +_____ _ ., __ _ _ + + + + +Pigmenturia, drugs + + + +History and examination +Urinalysis +Color, casts, crystals; microscopy for dysmorphicRBCs Urine protein/creatinine ratio, dipstick +Renal function tests, electrolytes +Ultrasound abdomen +Serum complement C3 + + +j Non-glomerular + + +24 hr urine protein· and creatinine ASO, anti-DNAse B +ANA, anti-dsDNA, ANCA Serum albumin, cholesterol + +Urine spot calcium, creatinine, protein, urate 24 hr urine calcium, urate, protein, creatinine Urine culture +Spiral CT abdomen Coagulation screen +Renal Doppler, magnetic resonance venography + + + + + +; 1o +- +4 + +Common causes j No etiology identified j Acute, chronic +glomerulonephritis Evaluate vision, hearing Common causes +Screen parents and siblings Hypercalciuria +Renal calculi +Urinary tract infection +Hydronephrosis +Consider kidney biopsy + +Fig. 16.6: Approach to evaluation of a patient with hematuria. The initial step in evaluation attempts to distinguish glomerular from nonglomerular causes of hematuria (see Table 16.3). Estimation of complement C3 is an important screening test for postinfectious glomerulonephritis. Patients with persistent glomerular hematuria might require kidney biopsy and/or screening for familial causes. ASO antistreptolysin 0, ANA +antinuclear antibody, anti dsDNA anti-double stranded DNA antibody, ANCA antineutrophil cytoplasmic antibody + + +Table 16.3: Features that distinguish glomerular from non-glomerular hematuria + +Features +Dysuria +Systemic complaints + + +Family history Hypertension, edema Abdominal mass Urine color Proteinuria Dysmorphic RBC RBC casts +Crystals + + +Glomerular causes + +Edema, pharyngitis, rash, arthralgia (postinfectious glomerulonephritis, lupus, Henoch-Schonlein purpura ) +Deafness, ren·a1 failure (Alport syndrome) Common +Absent +Brown, tea, cola 2+ or more >20% +Common Absent + +Non-glomerular causes +Suggests urethritis or cystitis Fever (UTI), loin pain (calculi) + + +Calculi (hypercalciuria) Rare +Wilms tumor, obstructive uropathy Bright red, clots +Trace, 1+ <15% Absent +May suggest calculi + + + +RBC red blood cells; UTI urinary tract infection + +is not urgently indicated and the patient kept under observation. + +Renal Biopsy +Renal biopsy should be done if hematuria is associated with persistent or heavy (3+ or more) proteinuria, history + + + +of renal disease in the family or evidence of chronic kidney +disease in the patient, or if renal impairment or hyper­ tension are seen on followup. A biopsy is also considered +in children showing persistent microscopic hematuria for two or more years even in the absence of the above features. This procedure is necessary to diagnose IgA +I Disorders of Kidney and Urinary Tract - + + +proteinuria, especially if associated with hematuria, should be promptly evaluated. + + + + + + + + + + + +Fig. 16.7: Phase contrast microscopy showing dysmorphic red cells (arrowhead). Normal red cells are also seen (arrow) + +nephropathy, Alport syndrome, thin basement membrane disease (typically presents as familial, benign hematuria) and chronic GN. The biopsy is evaluated by light, immunofluorescence and electron microscopy. + +Alport Syndrome +This condition is inherited in an X-linked manner, although autosomal transmission is known. Mutations in the gene encoding alpha subunit of collagen IV (COL4A5) result in persistent microscopic hematuria, moderate proteinuria and progressive kidney failure. A significant proportion show high frequency sensorineural deafness; ocular defects (lenticonus, cataract, macular changes) are often associated. Ultrastructural examination of renal biopsy shows variable thickness of glomerular basement membrane with lengths of marked attenuation to areas of lamination. Therapy is supportive, including the use of angiotensin converting enzyme inhibitors. The majority of male patients show progression to end stage kidney disease. + +Suggested Reading +Higashihara E, Nishiyama T, Horie S, et al; Working group for the +creation of hematuria guidelines. Hematuria: definition and screening +test methods. Int J Urol 2008;15:281-4 +Indian Pediatric Nephrology Group. Consensus statement on evalu­ +ation of hematuria. Indian Pediatr 2006;43:965-73 +Quigley R. Evaluation of hematuria and proteinuria: how should a +pediatrician proceed? Curr Opin Pediatr 2008;20:140-4 + +PROTEINURIA +The glomerular capillaries provide an effective barrier to filtration of proteins. Small amounts of protein are filtered but almost completely reabsorbed by the proximal tubule. Detection of more than trace amounts of protein in the urine is abnormal. However, the degree of proteinuria does not always reflect the severity of glomerular abnormality. Massive proteinuria occurs in minimal change nephrotic syndrome, in which glomeruli are normal or show mild changes. Persistent and heavy + +Quantitation of Proteinuria +Protein concentration of 100-1000 mg/m2 / day indicates mild to moderate proteinuria; more than that is heavy (nephrotic range) proteinuria. Accurate quantitative measurements of 24 hr urinary protein are not needed, if semiquantitative tests are done on a concentrated (first morning) specimen. Normally the protein to creatinine ratio, in the first morning urine specimen, is below 0.1 (mg/mg); a ratio of 0.1-2 indicates mild to moderate and >2 heavy proteinuria. The latter usually corresponds to 3+ or 4+ reaction on boiling or dipstick test. +Fever, dehydration and heavy exercise may cause transient and mild proteinuria. Mild proteinuria may occur in UTI, hydronephrosis and renal tuberculosis. Mild proteinuria in proximal tubular defects (e.g. Fanconi syndrome) is composed of low molecular weight proteins, while heavy proteinuria (predominantly albumin) indicates glomerular disease. +Important causes of asymptomatic proteinuria include orthostatic proteinuria, chronic glomerular diseases, reflux nephropathy, renal hypoplasia and rarely renal tubular disorders (Table 16.4). In orthostatic (postural) proteinuria, protein is absent in urine specimen collected after overnight recumbence. The pathogenesis of this condition is not clear but longterm outcome is good. Continued followup is necessary until proteinuria disappears. Chronic renal damage from vesicoureteric reflux and UTI may manifest with proteinuria. Several forms of glomerular diseases, especially focal segmental glomerulosclerosis, may cause persistent asymptomatic proteinuria; micro- + + +Table 16.4: Conditions presenting with proteinuria Glomerular proteinuria +Nephrotic syndrome (minimal change disease, focal segmental glomerulosclerosis, congenital nephrotic syndrome) +Membranoproliferative glomerulonephritis, membranous nephropathy +Hepatitis B and C nephropathy, HIV nephropathy Reflux nephropathy +Amyloidosis +Associated hematuria: Postinfectious glomerulonephritis, IgA nephropathy, Henoch-Schonlein nephritis, lupus nephritis, Alport syndrome +Tubular proteinuria +Drug induced nephropathy (analgesics) +Heavy metal nephropathy (e.g. gold, lead, cadmium) Renal tubular acidosis +Interstitial nephritis, pyelonephritis Intermittent or transient proteinuria Postural (orthostatic) +Fever Exercise +__ _ss_ en_t_ a_t_P_e _d_ia_t_ ic_ ________________________________ _ +i +s +r +_ +E +_ +_ + + +scopic hematuria is often associated. A renal biopsy is indicated in presence of persistent or heavy proteinuria. Longterm observation is necessary to monitor clinical course and renal function. Low salt diet and prolonged treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blockers are effective in reducing glomerular proteinuria. + +Suggested Reading +Rademacher ER, Sinaiko AR. Albuminuria in children. Curr Opin Nephrol Hyperten 2009;18:246-51 +Srivastava RN. Isolated asymptomatic proteinuria. Indian J Pediatr 2002,69: 1055-8 + +ACUTE GLOMERULONEPHRITIS +Acute glomerulonephritis (GN) is characterized by abrupt onset of hematuria, oliguria, edema and hypertension. The clinical severity varies, depending on histological involvement, salt and water retention and glomerular filtration rate. Mild disease may go undetected; severe cases have anuria, hypertensive encephalopathy and heart failure. The most common cause of acute GN is that following streptococcal infection (Table 16.5). Key investigations include renal function tests, urinalysis, serum complement C3 and titers of antistreptolysin. Renal biopsy is required if the presentation or course suggest a diagnosis other than poststreptococcal GN (Table 16.6). + +Poststreptococcal Glomerulonephritis +Acute GN following infection by group A beta-hemolytic streptococci is a common disorder. Streptococcal infection of the throat or skin precedes the onset of nephritis by 1 +to 4 weeks. Only a few strains of streptococci are nephritogenic, e.g. types 4 and 12 causing pharyngitis and type 49 causing pyoderma. + +Table 16.5: Etiology of the acute nephritic syndrome Postinfectious +Streptococci, staphylococci, pneumococci, meningococci, Treponema pallidum, Salmonella, leptospira +Plasmodium malariae, P. falciparum, toxoplasma, filaria Hepatitis B and C, cytomegalovirus, parvovirus, Epstein-Barr +virus, coxsackievirus, echovirus, varicella +Associated with severe infections; infection of shunts, prostheses, bacterial endocarditis +Systemic vasculitis +Henoch-Schonlein purpura +Microscopic polyarteritis, Wegener granulomatosis +Others +Membranoproliferative glomerulonephritis IgA nephropathy +Hereditary nephropathy Systemic lupus erythematosus + + +Table 16.6: Indns or nal sy in te ruphtis Systemic features. Fever, rash, joint pain, heart disease +Absence of serologic evidence of streptococcal infection; normal levels of C3 in the acute stage of illness +Mixed features of glomerulonephritis and nephrotic syndrome High blood levels of urea or presence of anuria requiring +dialysis (rapidly progressive GN) Delayed resolution +Oliguria, hypertension and/ or azotemia persisting past 7-10 days +Gross hematuria persisting past 3-4 weeks Nephrotic range proteinuria beyond 2 weeks Low C3 levels beyond 12 weeks +Persistent proteinuria beyond 6 months + +Pathology +On light microscopy, glomeruli are enlarged and ischemic and capillary loops narrowed, making glomeruli appear bloodless (Fig. 16.8A); there is proliferation of mesangial cells and neutrophil infiltration. Immunofluorescence shows granular deposits of IgG and complement (C3) along capillary walls (Fig. 16.8B). Electron microscopy shows deposits (humps) on the subepithelial side of the glomerular basement membrane. + +Clinical Features +Poststreptococcal GN involves school-age children, more commonly boys and is uncommon below 3 yr. Subclinical episodes are more common than overt disease, especially during epidemics. Patients may have mild proteinuria and microscopic hematuria. The onset is rapid, with puffiness around the eyes and pedal edema. Urine is cola-colored; hematuria is brief, often lasting only a few hours and does not persist beyond 1-2 weeks. While the degree of oliguria usually correlates with the disease severity, anuria is uncommon. Hypertension, present in over half the pati­ ents, resolves with loss of edema. Atypical presentations include (i) convulsions due to hypertensive encephal­ opathy; (ii) left ventricular failure and pulmonary edema, due to malignant hypertension and hypervolemia; (iii) acute kidney injury; and (iv) nephrotic syndrome. + +Laboratory Findings +Urine shows 1-2+ protein with red cells, and red cell and granular casts. White cells indicate glomerular inflam­ mation and should not be regarded as evidence of UTI. Hemodilution may result in normocytic anemia; ESR is raised. Blood levels of urea and creatinine are elevated reflecting renal impairment; hyponatremia and hyper­ kalemia occur with continuing oliguria. Chest X-ray may show prominent vascular markings suggesting hyper­ volemia. Serologic evidence for streptococcal infection is present in most patients with pharyngitis, though antibiotic therapy may blunt this response. ASO titer is increased in more than 80% patients; anti-DNase B is +Disorders of Kidney and Urinary Tract - + + + + + + + + + + + + + + + + + + +Figs 16.8A and B: (A) Poststreptococcal GN. Moderately severe proliferation and exudative changes with infiltration of neutrophils. Few open capillary lumina are seen; CB) lmmunofluorescence examination showing extensive fine granular deposition of lgG along the capillary wall and in mesangium with a starry sky appearance + + +elevated in cases of streptococcal skin infection. The titers decrease to low levels within 4-6 weeks. The level of serum C3 is low in 90% patients but normalizes by 8-12 weeks. Persistent low C3 levels indicate other forms of GN. + +Management +Patients with mild oliguria and normal blood pressure can be managed at home. Close attention to blood pressure and dietary intake is essential. Once acute GN has occurred, treatment with penicillin has no effect on the course of the disease, but may be given if active pharyngitis or pyoderma is present. The principles of management of patients with severe oliguria and acute kidney injury are discussed later. +Diet. The intake of sodium, potassium and fluids should be restricted until blood levels of urea reduce and urine output increases. Overhydration is a dangerous compli­ cation as it may increase hypertension and precipitate left ventricular failure. Patients with azoternia require accurate measurement of urine output and daily weight, and restriction of fluid intake to an amount equal to insensible losses and 24 hr urine output. +Diuretics. Patients showing modest edema are treated with oral frusemide at a dose of 1-3 mg/kg; the edema disappears with the return of renal function. Therapy with IV frusernide (2-4 mg/kg) is necessary in subjects with pulmonary edema. +Hypertension. Mild hypertension may be controlled by restriction of salt and water intake. Effective anti­ hypertensive agents include arnlodepine, nifedipine or diuretics. Beta-blockers and angiotensin converting enzyme inhibitors carry risk of hyperkalemia. Patients with hypertensive emergencies need prompt treatment with IV nitroprusside or labetalol. + +Lft ventricular failure. Hypertension should be controlled and IV frusemide given to induce diuresis, leading to improvement in heart failure. If diuresis is not noted, dialysis is initiated. Respiratory support with positive end­ expiratory pressure may be needed. + +Prolonged oliguria. Treatment, as outlined above, should be continued and levels of blood urea and electrolytes monitored. Dialysis is required in children with severe renal failure and prolonged oligoanuria, fluid overload and life­ threatening electrolyte disturbances. Occurrence of secondary infections should be avoided. + +Outcome and Prognosis +Acute poststreptococcal GN has an excellent prognosis in childhood. The symptoms begin to resolve in the first week with loss of edema and fall in blood pressure. Gross hematuria and significant proteinuria disappear within 2-weeks, although microscopic hematuria and slight proteinuria may persist for several months. Hypertension subsides within 2-3 weeks, but rarely may persist for several weeks. Patients with acute GN of nonstreptococcal etiology have variable and unpredictable outcome. These cases need close followup over several years with periodic urinalyses and measurements of blood pressure. + +Renal biopsy. A biopsy is rarely indicated in those suspected to have poststreptococcal GN except when renal function is severely impaired beyond 7-10 days or serum C3 remains depressed beyond 6-8 weeks. Patients with unresolving acute GN (persistent oliguria or azoternia past 7-10 days, hypertension or gross hematuria past 2-3 weeks) or those with features of a systemic illness (e.g. systemic lupus) require a kidney biopsy (Table 16.6). +__ ss_e____l P_e_d__a_tr__ ________________________________ +i +c +_ +s +i +n +t +i +a_ +E +_ + + +Crescen tic Glomerulonephritis +Rapidly progressive GN (RPGN) is defined as an acute nephritic illness accompanied by rapid loss of renal function over days to weeks. The histopathological correlate is the presence of crescents (crescentic GN) involving 50% or more glomeruli (Fig. 16.9) suggesting severe glomerular injury. The chief forms of RPGN are: (i) immune complex crescentic GN (nmunofluorescence showing immunoglobulin and C3 deposits; normal or low C3), (ii) pauci-immune crescentic GN (related to small vessel vasculitis; positive antineutrophil cytoplasmic antibodies; scant immune deposits) and (iii) anti­ glomerular basement membrane GN (with anti-GBM antibodies; linear IgG deposits). The severity of clinical and histological features often correlates. Patients with circumferential crescents involving more than 80% glomeruli show advanced renal failure; those with noncircumferential crescents in fewer glomeruli have an indolent course. Renal biopsy should be performed in all patients with severe nephritic features, which do not resolve within 1-2 weeks. +The outcome is related to histological severity and prompt institution of therapy. Without appropriate treat­ ment, patients are at risk for progressive renal failure. Satisfactory results have been obtained with initial administration of IV and oral corticosteroids and IV cyclo­ phosphamide, followed by maintenance immunosup­ pression. Plasmapheresis is recommended in patients with pauci-immune crescentic GN and Goodpasture syndrome. + +Nephriit s in Henoch-Schonlein Pur pura +Henoch-Schonlein purpura (HSP) is the most common vasculitis in children (Fig. 16.10). Mild renal involvement indicated by microscopic hematuria and mild proteinuria is common. Serum IgA levels may be elevated. Renal + + + + + + + + + + + + + + + + + + +Fig. 16.9: Large cellular crescent with compression of glomerular tuft (Masson trichome X 200) + + + + + + + + + + + + + + + + +Fig. 16.10: Henoch-Schonlein purpura in a 6-yr-old girl admitted with severe abdominal pain. Note purpuric rash over the lower limbs + +biopsy shows mesangial proliferation with mesangial deposition of IgA. Most patients recover without any specific treatment. However, longterm observation is necessary to detect insidious renal damage. Rarely a patient may present with nephritic or nephrotic syndrome, hypertension, azotemia and crescentic GN. Therapy with a combination of oral/IV corticosteroids and cyclophos­ phamide initially, followed by maintenance steroids and azathioprine is recommended. Longterm outcome depends on the severity of renal manifestations. + +l m munoglobulin A Nephropathy +Predominant deposition of IgA in the glomeruli, chiefly in the mesangium and occasionally in capillary walls is characteristic. The usual clinical manifestation is recurrent episodes of gross hematuria following upper respiratory infections; each episode lasts for 2-5 days. In between these episodes, microscopic hematuria and mild protei­ nuria may persist. An acute nephritic or nephrotic syndrome is rarely the initial manifestation. Renal histo­ logy shows mesangial proliferation of varying severity. Patients with hematuria and non-nephrotic proteinuria are treated using angiotensin converting enzyme inhi­ bitors. Therapy with corticosteroids and alkylating agents is indicated in patients with nephrotic range proteinuria or deranged renal function. + +Lupus Nephritis +Variable clinical and renal histological patterns are observed in patients with systemic lupus erythematosus. Asymptomatic proteinuria and/ or hematuria, acute nephritic syndrome and nephrotic syndrome are most common. Rarely renal involvement may be manifested as rapidly progressive GN. Renal biopsy may show almost normal glomeruli, focal or diffuse proliferative GN or membranous nephropathy. Immunofluorescence studies show mesangial and capillary wall deposits of IgG and +Disorders of Kidney and Urinary Tract - + + + +C3 and usually Clq and IgA. Antinuclear and double­ stranded DNA autoantibodies are present in most cases with lupus nephritis; C3 levels are reduced. +Remissions and relapses and progressive renal damage are characteristic. Infections and end stage renal disease are the chief cause of mortality. Judicious use of cortico­ steroids, cytotoxic agents (cyclophosphamide, myco­ phenolate mofetil and azathioprine), calcineurin inhibitors (cyclosporine, tacrolimus) and monoclonal antibodies and prompt treatment of infections has improved outcomes. + +Suggested Reading +Brogan P, Bagga A Leukocytoclastic vasculitis. In: Cassidy JT, Petty RE, Laxer RM, Lindsay CB, eds. Textbook of Pediatric Rheumatology, 6th ed. Philadelphia, Saunders Elsevier 2011;483-97 +Brogan P, Eleftheriou D, Dillon M. Small vessel vasculitis. Pediatr Nephrol 2010:25;1025-35 +Gulati A, Bagga A. Management of lupus nephritis. Indian J Rheumatol 2012; ?(Suppl 1):69-79 +Hogg RJ. Idiopathic immunoglobulin A nephropathy in children and adolescents. Pediatr Nephrol 2010;25:823-9 + +NEPHROTIC SYNDROME +Nephrotic syndrome is characterized by massive pro­ teinuria, hypoalbuminemia and edema; hyperlipidemia is often associated. Some patients show hematuria and hypertension. Heavy proteinuria (more than 1 g/m2 per day) is the underlying abnormality, leading to hypoalbuminemia (serum albumin below 2.5 g/ dl). The resultant fall in plasma oncotic pressure leads to interstitial edema and hypovolemia. This stimulates the renin­ angiotensin-aldosterone axis and antidiuretic hormone secretion that enhances sodium and water retention. The pathogenesis of edema may however be different in patients with significant glomerular lesions, who show primary sodium retention and expanded intravascular volume. Hypoalbuminemia also induces hepatic synthesis of �-lipoproteins resulting in hypercholesterolemia. +More than 90% of childhood nephrotic syndrome is primary (or idiopathic). Other causes such as amyloidosis, vasculitis, systemic lupus erythematosus, postinfectious GN and hepatitis B nephropathy are infrequent. Nephrotic syndrome in children can be divided into two groups based on renal histological characteristics: (i) minimal change nephrotic syndrome (MCNS); and (ii) nephrotic syndrome with significant lesions (Table 16.7). +Steroid sensitive nephrotic syndrome (which is usually MCNS) has a satisfactory longterm outcome. In contrast, the steroid resistant form (usually associated with significant glomerular lesions) has less satisfactory course and a significant proportion progress to chronic renal failure. + +STEROID SENSITIVE NEPHROTIC SYNDROME +MCNS accounts for 80% cases of nephrotic syndrome in children. Renal biopsy does not show significant + + +Table 16.7: Features of idiopathic nephrotic syndrome Features Minimal lesion Signficant lesions +Age at onset 2-6 yr Older children Sex incidence Higher in boys Equal Hematuria Rare Usual +Blood Normal Normal or increased pressure +GFR Normal Normal or decreased Renal biopsy Normal glomeruli; Changes of varying +mild mesangial severity;C3, proliferation; rnunoglobulin often IgM deposits deposits +SerumC3 Normal Low in MPGN Selectivity of High Low +proteinuria +Response to Remission in >95% Unsatisfactory steroids +Prognosis Good; relapses stop Variable progression of by second decade renal damage +MPGN membranoproliferative glomerulonephritis + +abnormalities on light microscopy (Fig. 16.llA). Electron microscopy shows nonspecific obliteration of epithelial foot processes. Immunofluorescence studies do not demonstrate deposition of immune reactants except occasional mesangial IgM. On the other hand, patients with focal segmental glomerulosclerosis (FSGS) show evidence of sclerosis involving a segment of the glome­ rular tuft (Fig. 16.llB). The pathogenesis of MCNS is obscure. There is evidence to suggest perturbation of cell mediated immunity, which through yet undefined mechanisms alters the permselectivity of the glomerular filter, resulting in massive proteinuria. A proportion of patients have a primary abnormality of the epithelial foot processes (podocytes). + +Clinical Features +The onset is insidious with edema first noticed around the eyes and subsequently on legs. It is soft and pits easily on pressure. Gradually edema becomes generalized, with ascites, hydrothorax and hydrocele (Fig. 16.12). With increasing edema, urine output may fall. The blood pressure is usually normal; sustained elevation suggests the possibility of significant glomerular lesions. The bloated appearance and relative well-being of the child is misleading and after the loss of edema, severe muscle wasting is revealed. Infections may be present at the onset and during relapses. + +Laboratory Findings +Urine examination shows heavy (3-4+) proteinuria. Gross hematuria or persistent microscopic hematuria suggests the likelihood of significant glomerular lesions; hyaline and granular casts are present. Serum albumin is low and values below 1 g/ dl are often obtained. Hypercholestero­ lemia may impart a milky appearance to the plasma. Blood +-__E__e_ ialPediatic_________________________________ +ss +n +t +_ ____ +_ +r +_ _____ +s + + + + + + + + + + + + + + + + + + +Figs 16.11 A and B: (A) Renal histology in a 4-yr-old boy with steroid dependent nephrotic syndrome. There is normal morphology of glomerular capillary loops, mesangial matrix and cells suggestive of minimal change disease; (B) histological features in a 6-yr-old girl with steroid resistant nephrotic syndrome secondary to focal segmental glomerulosclerosis. Note the hilar sclerosis involving large areas of the glomerulus and adhesions to the Bowman's capsule + + + + + + + + + + + + + + + + + + + +Fig. 16.12: An 8-yr-old boy with steroid dependent nephrotic syndrome. Anasarca is seen affecting upper limbs (including dorsa of hands), trunk and ascites. Note the cushingoid features and striae on lower abdominal wall and upper legs +urea and creatinine values are within the normal range except when there is hypovolemia and fall in renal perfusion. +Blood levels of IgG are low and those of IgM elevated; C3 level is normal. The severity of glomerular damage is reflected in the passage of proteins of large molecular weight, chiefly globulin. Protein selectivity is the ratio of clearance of high molecular weight (e.g. IgG) to low molecular weight proteins (e.g. transferrin, albumin). A low ratio indicates highly selective proteinuria, as in MCNS. However, this information does not offer diagnostic help. + +Evaluations considered at onset of nephrotic syndrome include: (i) urinalysis for proteinuria, red cells, casts; (ii) blood levels of urea, creatinine, albumin, cholesterol; (iii) complete blood counts and (iv) tuberculin test. Depen­ ding on clinical and laboratory findings, the following additional tests may be required: (i) C3 and antistrepto­ lysin O (gross or persistent microscopic hematuria); (ii) chest X-ray (positive tuberculin test; history of contact with tuberculosis); (iii) hepatitis B surface antigen (recent jaundice, raised levels of transaminases); (iv) antinuclear antibodies (suspected systemic lupus erythematosus); and (v) urine culture (suspected urinary tract infection). A renal biopsy is not required to confirm the diagnosis of MCNS prior to starting treatment. A biopsy is recom­ mended in children with atypical features at the onset (age below 12 months, gross or persistent microscopic hema­ turia, low blood C3, hypertension or impaired renal function). Patients who continue to show nephrotic range proteinuria despite appropriate steroid therapy require a biopsy to determine the underlying disorder. + +Management of Initial Episode +The child should receive a high protein diet. Salt is restric­ ted to the amount in usual cooking with no extra salt given. Any associated infection is treated. The presence of tuberculosis should be looked for. Diuretics are adminis­ tered only if edema is significant. F rusemide (1-4 mg/kg/ day in 2 divided doses) alone or with an aldosterone antagonist, spironolactone (2-3 mg/kg/day in 2 divided doses) is adequate. Diuretics should be used cautiously and overzealous fluid loss avoided. Therapy with cortico­ steroids results in abolition of proteinuria (remission) usually by 10-14 days, diuresis and loss of edema. +Disorders of Kidney and Urinary Tract + + + +The first episode of nephrotic syndrome should be treated adequately, both in terms of dose and duration of corticosteroids, since this is considered an important determinant of longterm course. Only prednisolone and prednisone are of proven benefit in the treatment of proteinuria. Either of these agents is given at a dose of 2 mg/kg per day (maximum 60 mg) in single or divided doses for 6 weeks, followed by 1.5 mg/kg (maximum 40 mg) as a single morning dose on alternate days for the next 6 weeks. Therapy with corticosteroids is then stopped. While some experts propose that therapy with corticosteroids should not be stopped abruptly and tapered over the next 8-12 weeks, the benefits of pro­ longed therapy need to be balanced by the risk of steroid adverse effects. + +Parent Education +The parents should be explained about the disease and the usual outcome and their cooperation ensured. They are taught how to examine urine for protein, which should be done periodically to detect a relapse early. During the periods of remission, no dietary restrictions are imposed. + +Subsequent Course +A small proportion of patients have only a single episode of the illness, while the majority shows relapses. Some patients have three or less relapses in a year (infrequent relapsers), while others have four or more relapses (frequent relapsers) (Table 16.8). About 15% remain in remission while on prednisolone therapy and relapse whenever the dose is reduced or within 2 weeks of its discontinuation (steroid dependent). About 10-15% patients either do not respond to the initial treatment with prednisolone, or do so transiently and later cease to respond (steroid resistant). + +Management of Relapse +Relapses are often triggered by minor infections. Symptomatic therapy of infectious illness might result in remission of low grade (1-2+) proteinuria. However, persistence of 3-4+ proteinuria requires treatment for + +Table 16.8: Important definitions to clarify course of nephrotic syndrome +Remission: Urine albumin nil or trace (or proteinuria <4 mg/ m2 /hr) for 3 consecutive early morning specimens +Relapse: Urine albumin 3+ or 4+ (or proteinuria >40 mg/m2/ hr) for 3 consecutive early morning specimens, having been in remission previously +Frequent relapses: Two or more relapses in initial six months or four or more relapses in any twelve months +Steroid dependence: Two consecutive relapses when on alternate day steroids or within 14 days of its discontinuation +Steroid resistance: Absence of remission despite therapy with daily prednisolone at a dose of 2 mg/kg per day for 4 weeks and alternate day for next 4 weeks. + + +relapse. Prednisolone is given at a dose of 2 mg/kg/ day until protein is negative/trace for three consecutive days, and then on alternate days at a dose of 1.5 mg/kg for 4 weeks. Thus, treatment for a relapse usually lasts for 5-6 weeks and there is no evidence that its prolongation affects the outcome. +The first 2-3 relapses are treated in the manner described above. Once the pattern of relapses is known, therapy is individualized. Patients with infrequent relapses continue to receive treatment for individual relapses as outlined above. + +Frequent Relapses and Steroid Dependence +Patients with frequent relapses or steroid dependence require prolonged treatment in order to maintain disease remission. + +Longterm Alternate Day Predniso/one +Following treatment of a relapse, the dose of prednisolone is tapered to maintain the patient in remission; usually a small dose is given on alternate days for 9-18 months. This strategy is effective in maintaining remission in many patients. Since infections precipitate relapses, adminis­ tering the same small dose daily for 5-7 days starting at onset of infections may prevent relapses. However, relapses, while on this therapy, are treated with daily prednisolone at 2 mg/kg/day until remission, after which alternate day therapy is resumed at 1.5 mg/kg. Patients with repeated relapses, while on longterm therapy, should be considered for treatment with a steroid sparing agent. + +Steroid Sparing Agents +The additional use of an alternative agent should be considered in patients with: (i) prednisolone threshold (for maintaining remission) higher than 0.5-0.7 mg/kg on alternate days, or (ii) features of corticosteroid toxicity (growth failure, hypertension and cataract). The agents used, usually in successive order, are listed below and in Table 16.9. +Levamisole. This immunomodulator is effective in reducing relapses in a proportion of patients with frequent relapsing or steroid dependent nephrotic syndrome. After inducing remission, levamisole is administered at a dose of 2-2.5 mg/kg on alternate days. Alternate day predniso­ lone is given in decreasing doses, until a dose of 0.3-0.5 mg/kg is reached, for 3-6 months; it is occasionally possible to discontinue steroids altogether. Treatment with levamisole is given for 1-2 yr or longer. The chief side effect is leukopenia, which should be monitored every 2 months; others include flu like symptoms and rash. +Cyclophosphamide. Treatment with alkylating agents and alternate day prednisolone is effective in many patients with frequent relapsing or steroid dependent nephrotic syndrome. A 12-week course of treatment may induce long-lasting remission in 30-40% cases. Side effects include +___ _s_s_ _e_t_a_i_P_e_d_i_at_r_is__________________________________ _ +i +n +E +c + +Table 16. 9: Therapy for steroid sensitive nephrotic syndrome + +Agent +Prednisolone + + +Dose +Maintain on 0.3-0.7 mg/kg on alternate days + +Duration +9-18 mo + + +Adverse effects +Cushingoid body habitus, hypertension, short stature, cataract, hirsutism + + + +Levamisole 2-2.5 mg/kg on alternate days Cy clop hos- 2-2.5 mg/kg/day +phamide* + +Mycophenolate 600-1000 mg/m2/day or mofetil 20-25 mg/kg/day +Cyclosporine (CyA)* CyA: 4-5 mg/kg/day +or Tacrolimus (Tac)* Tac: 0.1-0.2 mg/kg/day + + + +Rituximab* 375 mg/m2 IV once a week + +1-2 yr +12 weeks + + +1-3 yr + +12-36 mo + + + +2-3 doses + + +Leukopenia, rash, flu-like symptoms Leukopenia; alopecia; gonadal toxicity; nail +discoloration (hemorrhagic cystitis; nausea and vomiting are more common with IV administration) +Gastrointestinal discomfort, diarrhea; leukopenia + +Acute and chronic nephrotoxicity, elevated transaminases (both agents); hirsutism, gum hyperplasia, hypertension or hyperlipidemia (CsA > Tac); hyperglycemia, neurotoxicity with headache and seizures (Tac > CsA) +Infusion reactions (fever, rash, bronchospasm); hypogammaglobulinemia, neutropenia + + +• Preferred earlier if relapses are life threatening (associated with peritonitis, other serious infections or thrombosis) or in presence of significant steroid toxicity + + +leukopenia, nausea and vomiting; a high fluid intake is ensured to prevent hemorrhagic cystitis. Alkylating agents are associated with a risk of gonadal toxicity and malignancies, although at the doses and duration used these risks are minimal. Another alkylating agent, chlorambucil has significant additional toxicities and a low margin of safety, and is not recommended. +Mycophenolate mofetil. Prolonged treatment with this agent is useful in reducing relapse rates and corticosteroid sparing. The lack of renal, hemodynnic and metabolic toxicity makes it an alternative to calcineurin inhibitors. Chief side effects include gastrointestinal discomfort, diarrhea and leukopenia. The dose of the medication is 600-1000 mg/m2/day or 20-25 mg/kg/day in two divided doses for 12-36 months. Tapering doses of prednisolone are given for 6-12 months. +Cyclosporine and tacrolimus. Therapy with either of these agents is indicated in patients that fail to benefit with levamisole, cyclophosphamide and/or mycophenolate mofetil. Treatment may be associated with significant adverse effects. Cyclosporine A (4-5 mg/kg/day) or tacrolimus (0.1-0.2 mg/kg/day) are administered, in two divided doses, for 12-24 months aiming for respective trough levels of 80-120 ng/ml and 3-7 ng/ml. Both agents have strong steroid sparing potential, with steroid discontinuation achieved in most patients over 6-9 months. +Adverse effects are common and include acute and chronic nephrotoxicity. A renal biopsy is done after 2-3 yr of continuous therapy. Patients receiving cyclosporine have cosmetic side effects (hirsutism, gum hyperplasia), hypertension and hypercholesterolemia. Treatment with tacrolimus is associated with risk of hyperglycemia, elevated transaminases, diarrhea, tremors, headache and seizures. + +Rituximab. This monoclonal anti-CD20 antibody has been used with success in patients with steroid dependent nephrotic syndrome, with remission lasting 6-18 months. This agent appears to be useful in patients who fail to respond or show toxicity with other therapies. + +Complications in Nephrotic Syndrome +The patient should be maintained in remission, as far as possible. Relapses should be promptly treated so that the child does not develop more than minimal edema. Several complications that are associated with massive edema and ascites. + +Edema +Edema is controlled with salt restriction and oral hydro­ chlorothiazide or frusemide for a few days. Salt must not be totally stopped and the usual amounts used in cooking should be allowed. For massive edema, higher doses of frusemide along with spironolactone are needed. Infusion of albumin may be necessary in intractable cases where serum albumin levels are extremely low causing poor renal perfusion and oliguria. + +Infections +Nephrotic syndrome and steroid therapy render children susceptible to infections. Infection with S. pneumoniae, gram-negative organisms and varicella are common. Children present with serious infections, e.g. peritonitis, cellulitis, pneumonia and meningitis. Peritonitis may manifest with low grade fever, diarrhea and abdominal discomfort. Patients with varicella should receive oral acyclovir for 7 days; severe illness requires administration of IV acyclovir. Immunization with pneumococcal and varicella vaccines is advised once the patient is off steroids for 4 weeks. +Disorders of Kidney and Urinary Tract + + + +Thrombotic Complications +Patients with nephrotic syndrome are at risk for throm­ bosis involving renal, pulmonary and cerebral veins. Aggressive use of diuretics, venepuncture of deep veins and hypovolemia increase the risk of this complication. Treatment with low molecular weight heparin followed by oral anticoagulants is recommended. + +Hypovolemia and Acute Renal Failure +Hypovolemia may occur during a severe disease relapse or following administration of diuretics, particularly in children with poor oral intake, diarrhea and vomiting. Features include abdominal pain, lethargy, dizziness and leg cramps, tachycardia, hypotension, delayed capillary refill, low volume pulses and clammy distal extremities. Elevated ratio of blood urea to creatinine, high hematocrit, urine sodium <20 mEq/1, fractional excretion of sodium 0.2-0.4%and urinary potassium index [urineK+ /(urineK+ + urine Na+)] >0.6 suggest the presence of hypovolemia. Therapy with diuretics should be discontinued. Patients require admission and rapid infusion of normal saline (10-20 ml/kg) over 20-30 min. Those who do not respond to two boluses of saline should receive infusion of 5% albumin (10-15 ml/kg) or 20% albumin (0.5-1 g/kg). + +Steroid Toxicity +Repeated and prolonged courses of steroids often result in significant toxicity, characterized by cushingoid features, short stature, hypertension, osteoporosis and subcapsular cataract. Timely use of steroid sparing agents (levamisole, alkylating agents, cyclosporin) are recommended. + +Longterm Outcome \ No newline at end of file