Review Article

COMPLICATIONS OF NEPHROTIC SYNDROME IN CHILDREN

Rajan Arora* and R.N. Srivastava*** Registrar, **Senior Consultant, Department of Pediatric Nephrology, Indraprastha Apollo Hospitals,

Sarita Vhar, New Delhi 110 076, India.Correspondance to: Dr. R.N. Srivastava, Consultant Pediatric Nephrologist , Indraprastha Apollo Hospitals,

Sarita Vihar, New Delhi 110 076, India.e-mail: rnsri@vsnl.net

Nephrotic syndrome is an important chronic disease in children, characterized by minimal change disease inthe majority. Untreated nephrotic syndrome may cause numerous complications, such as, infections,hypovolemia, hypercoagulability, hyperlipidemia, anemia, growth and development delays. The morbidity andoccasional mortality is from inadequate management and complications and not due to renal failure. Expertiseand clinical judgement as well as cooperation of the family are crucial for optimal management and a favorableoutcome.

Key words: Nephrotic syndrome, Children, Complications.

INTRODUCTION

NEPHROTIC syndrome (NS) is an important chronicdisorder, characterized by alterations of permselectivityat the glomerular capillary wall, resulting in its inability torestrict he urinary loss of protein. Nephrotic patients areprone to a number of extra renal and renal complications.Two main categories are to be considered those due to thedisease itself arising from hypoalbuminemia [1,2] andthose due to the treatment, mainly corticosteroids, butalso alkylating agents and cyclosporine. The more severethe hypoalbuminemia is, the higher the risk ofcomplications. For these reason children with steroidresistant NS and infants with congenital NS are moresusceptible to complications than those with steroidsensitive NS.

Infections

Infections [2,3] still remain one of the most serious lifethreatening complications in children with NS, especiallyin developing countries such as India. Besides being thecommonest cause of mortality infections result insignificant morbidity and may be responsible for a poorresponse to steroid therapy or induce relapse in a childwho in remission. Increased predisposition to infectionsoccurs due to loss of immunoglobulin, complement andproperidin, altered T cell functions immunosuppressivetherapy and presence of edema.

Common infections include peritonitis, cellulitis,pneumonia and upper respiratory tract viral infections.

Viral and bacterial infections may precipitate relapses.Empiric therapy should be started to protect the mostcommon pathogens, E.coli and S. pneumoniae, in theevent of suspected infection (Table 1).

Varicella may be a severe illness in patients withNS who are immunocompromised. Patients who areunimmunised and exposed to a patient having chicken-pox are recommended prophylaxis with Varicella zosterimmunoglobin. Immunocompromised patients whodevelop varicella should be treated with oral orintravenous acyclovir depending on the severity ofinfection. Treatment with steroids is discontinued.

Tuberculosis is an important infectious complicationin children with NS. It may interfere with the response tosteroid therapy and or accelerate the progression of renalfailure in these patients [4]. The conventional diagnostictests such as mantoux and AFB isolation are oftenunhelpful, and a high index of suspicion is required.Patients with NS, who are mantoux positive but show noevidence of disease, should be closely observed whilereceiving prednisolone. Those having evidence of activetuberculosis should receive standard antituberculartherapy for 2 weeks before starting steroids.

Patients with steroid responsive NS and massiveascites may receive prophylaxis with penicillin V in adose of 125 to 250 mg twice daily until the ascites hasresolved. However, there is no evidence that routine useof antibiotic prophylaxis leads to reduction in theoccurrence of infections in these patients.

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Children with NS are susceptible to infections withencapsulated organisms. Haemophilus influenzae,varicella, hepatitis and pneumococcal vaccinations arerecommended in all children with NS. The vaccineshould be given during remission and preferably whenthe child is not receiving daily prednisolone. Inactivatedor killed vaccines are safe [5], but live vaccines should beadministered once the child is off steroids for 6 weeks. Abooster dose is recommended every five years for thosechildren who had the initial pneumococcal vaccinebefore the age of five years but continues to relapse.Patients in remission and not on steroid therapy shouldreceive varicella vaccine in a 2 dose schedule,administered 4 weeks apart.

Thromboembolic complications (TEC)

Children with NS are at increased (1.8%-5%) risk forvenous and rarely arterial thrombosis [3,6] but it isunderestimated because of possible asymptomaticevents. Though the overall risk is lower as compared to

the adults, there is evidence that implications of suchevents are greater in children. Typically thromboticevents complicating nephrotic syndrome have beenreported in pediatric patients with congenital NS,minimal change disease and focal segmental glomerulo-sclerosis. This risk has been attributed to a variety ofintrinsic factors, such as coagulation protein abnormali-ties, impaired fibrinolysis, thrombocytosis, plateletaggregation as well as extrinsic factors such asdehydration, trauma, infections, immobilization, diureticand corticosteroid use. Diuretics should be usedjudiciously and puncture of deep vessels is to be avoided.

Renal vein thrombosis is suspected in a patientwith oligoanuria, hematuria, and flank pain especiallyfollowing an episode of dehydration. Ultrasoundexamination of the abdomen might show large kidneysand thrombi in renal veins.

Thrombosis is not limited to renal veins although thissite predominates. Femoral arterial thrombosis may

Table 1 : Clinical features and management of common infections

Infection Clinical features Common organisms Antibiotics Duration of t/t

Peritonitis Pain abdomen, S. pneumoniae, Penicillin / ampicillin and 10-14 daysabdominal S. pyrogenes, E.coli, aminogycoside ortenderness and S. aureus cefotaxime / ceftriaxonevomiting. fever ( ascitic fluid >100may be absent white cells/min3, 50%

neutrophils)Pneumonia Fever, cough, S. pneumoniae, Oral amoxicillin, 7-10 days

tachypnea, H. influenzae erythromycin andcrepitations aminogylcoside or

cefotaxime/ ceftriaxoneUrinary tract Frequency of E.coli, Klebsiella spp. Amoxicillin, cephalexin, 7-10 daysinfections micturition, Proteus spp. cotrimoxazole,

dysuria,fever, Coamoxiclav,turbid urine Amikacin

Cellulitis Redness, GroupA Streptococci, Ampicillin and an 7-10 daysinduration, H. influenzae Aminogycoside ortenderness cefotaxime / ceftriaxone

Fungal Pulmonary Candida, Skin, mucosa: 7-10 daysinfections infiltrate, persistent Aspergillus spp. Fluconazole systemic 14-21 days

fever unresponsive Amphotericin Bto antibacterialtherapy,sputum/urineshowing septatehyphae

Initial therapy may be parenteral for 5 days; once patient is nontoxicand accepting orally, the medication may be administeredorally.

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occasionally occur. Deep vein thrombosis of the calfveins is less common in children but may lead topulmonary embolism, and sub clinical episodes may bemore common than is presently appreciated. Saggitalsinus and cortical venous thrombosis may followepisodes of diarrhea and present with convulsions,vomiting, altered sensorium and neurological deficits.Doppler studies and cranial CT scan are useful inconfirming the diagnosis.

Patients with clinical and radiological evidence ofthrombosis require urgent treatment under the super-vision of a specialist. The treatment is supportive andconsists of early mobilization, treatment of sepsis,prompt treatment of dehydration and cautious use ofanticoagulants. Most centres prefer low molecularweight heparin, as it is effective and convenient toadminister in 1-2 divided doses subcutaneously. Initialtherapy with heparin is followed by oral warfarin for 6months or longer. The role of thrombolytic therapy orsurgical thrombectomy is not established. Nephroticpatients with a history of TEC events or steroid nonresponsive NS should be put on prophylaxis with anindirect anticoagulant during the new relapses untilremission is achieved the patient is off steroids.

Hypovolemia

Hypovolemia occurs when hypoalbuminemiadecreases the plasma oncotic pressure. It is generallyobserved only when the patient’s serum albumin is lessthan 1.5 g/dL. This complication can occur due tounsupervised use of diuretics especially if accompaniedby septicemia, diarrhea or vomiting. The clinical featuresinclude vomiting, abdominal pain, tachycardia, coldextremities and poor capillary refill. Hypotension is a latefeature. Blood levels of urea and uric acid are elevated. Aurinary sodium of <10 mmol / L is a useful investigationto confirm hypovolemia. A rapid infusion of normalsaline or plasma in a dose of 15-20 mL/kg or albumin1 g/kg/dose is required. The blood pressure is to bemonitored carefully. Albumin should be used withcaution if the child is hypertensive because of the risk ofpulmonary edema. Monitor pulse rate, blood pressure,jugular venous pressure and chest X-ray for cardio-megaly.

Once adequate hydration is achieved, but the childremains oliguric, a single dose of frusemide 1-2 mg/kg IVmay be given. In case no urine is passed despite all thesemeasures, the diagnosis of acute renal failure issuspected.

Acute renal failure

ARF in nephrotic syndrome may develop in theabsence of glomerular inflammation and may occureither at the time of presentation or much later. Causesinclude rapid progression of original glomerular disease,bilateral renal vein thrombosis, AIN due to antibioticsand non-steroidal anti-inflammatory drugs (NSAIDs)and acute tubular necrosis secondary to sepsis orhypovolemia [7,8]. However, the most common cause ofARF is prerenal azotemia complicating acutegastroenteritis or aggressive diuretic therapy forcontrolling of edema. Treatment involves correction ofblood volume depletion by albumin infusion followed byfrusemide 1-2 mg/kg IV. The outcome is usuallyfavourable but dialysis might be occasionally required.

Hyperlipidemia

Hyperlipidemia, in NS is characterized by elevatedtotal plasma cholesterol or more specifically LDLcholesterol. In most patients with steroid sensitive NS it istransient, disappears with remission and does not havelong term implications [5]. However, raised blood levelsof lipids may persist in patients with steroid resistantcases and potentially contribute to cardiovascularmorbidity and progression of glomerulosclerosis [9].Patients are encouraged to achieve a normal weight forheight; diet should have no more than 30% of fat and aratio of 1:1 polyunsaturated to saturated fatty acids. Anymedication that increases lipids should be discontinued.While there are no clear guidelines for the use of statins,short term efficacy and safety of these agents have beendemonstrated in children [10].

Hypertension

Hypertension may signify an acute nephritis or maybe part of the hyperreniremic state NS induced byhypovolemia and reduced perfusion of the kidneys. Itmay be noted at the onset of nephrotic syndrome oroccur due to steroid toxicity. Therapy may be initiatedwith ACE inhibitors, calcium channel or β-adrenergicblockers.

Failure to thrive

It may develop in patients with chronic edema,including ascites and pleural effusion. It may be causedby anorexia, hypoproteinemia, increased proteincatabolism, or frequent infectious complications. Edemaof the gut may cause defective absorption, leadingto chronic malnutrition. In addition, growth and

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development are delayed during the active phase ofnephrosis, however normal growth typically resumeswith disease remission. A balanced diet adequate inprotein and calories is recommended. The child shouldreceive 1.5-2 g/kg of proteins and those with persistentproteinuria require 2-2.5 g/kg of proteins daily [5]. Notmore than 30% calories should be derived from fat andsaturated fats avoided. Carbohydrates are best given ascomplex forms (starch and maltodextrin). A modestreduction (1-2 g per day) is advised in the presence ofmarked edema. Salt should not be added to salads andfruits; snacks containing high salt are avoided duringthese periods. Corticosteroids stimulate the appetite, andadvice should be given about ensuring physical activityand preventing excessive weight gain.

Metabolic complications

Untreated patients may be at increase risk of anemiasecondary to impaired biosynthesis of erythropoietin,urinary iron losses and concurrent angiotensinconverting enzyme inhibitor therapy. Transferin loss maylead to anemia resistant to iron therapy. Serum iron levelsmust be monitored as both iron and transferin may be lowin persistent nephrotic syndrome. The incidence ofhyponatremia in nephrotic syndrome is lower than ineither congestive heart failure or cirrhosis most likely as aconsequence of higher blood pressure, higher GFR, andmore modest impairment in Na+ and water excretion thanin the other group of patients. Tetany, is also a reportedcomplication. A positive Chvostek or trousseau sign maybe present. Supplementation with vitamin D and calciummay be useful for patients receiving corticosteroidtherapy. Attention to electrolyte balance in patientsreceiving diuretic therapy may result in fewercomplications.

Complications due to treatment

Prolonged high dose steroid therapy may be associ-ated with significant side effects. Steroids result in an in-creased appetite, cushingoid features, adrenal suppres-sion, impaired growth, behavior changes, gastritis, saltand water retention, hypertension, striae, cataracts,myopathy, metabolic alkalosis, bone demineralization,aseptic bone necrosis, diabetes, decreased immunity andsubsequent increased risk of infection. Patients should bemonitored for signs and symptoms of infection, such asfever and elevated white blood cell count. Examinationfor cushingoid features, monthly record of blood pres-sure, six monthly record of height and weight, assessmentfor bone demineralization and yearly evaluation for cata-

ract are recommended. Precautions and prophylaxis forsurgery, anaesthesia, and intercurrent illness afterstopping steroids are required for 3 months.

Cyclophosphamide : gonadal toxicity (azoospermia,ovarian fibrosis and infertility) if cumulative dose is>250 mg/kg, marrow suppression, alopecia, haemorr-hagic cystitis, infection and gastrointestinal symptoms.Chlorambucil results in increased risk of malignancy,Gonadal toxicity if cumulative dose is >10 mg/kg whilecyclosporine has a nephtrotoxic potential.

CONCLUSION

Pediatrician should be aware of the complicationsthat may arise in patients with NS. These complicationsmay develop in steroid responsive as well as steroidresistant NS. Early diagnosis helps in the timely andaccurate management of these problems. In a largeproportion of cases the occurrence of complications isiatrogenic, that is dependant on medical errors and orinsufficient communication between family and doctorand thus avoidable. Supportive care in terms of balanceddiet, immunizations and patient and parent education andmotivation is an important aspect in the management ofchildren with NS. Adequate information about thedisease, associated complications and the expectedcourse should be provided to them for a favourableoutcome.

REFERENCES

1. Broden. J. Management of nephrotic syndrome in children.Clin Immunother 1996; 5: 175-192.

2. Harris RC. Extrarenal complications of the nephroticsyndrome. Am J Kidney Dis 1994; 23: 477-497.

3. Lilova M,Velichkov NI. Budd Chiarri syndrome and inferiorvena cava thrombosis in a nephrotic child. Pediatr Nephrol2000; 14: 412-415.

4. Kala U, Milner NS, Lacobs D, Thompson PD. Impact ofTuberculosis in children with idiopathic nephriticsyndrome. Pediatr Nephrol 1993; 7: 392-395.

5. Bagga A, Sharma A, Srivastava RN. Levamisole therapy incorticosteroid dependant nephrotic syndrome. PediatrNephrol 1997; 11: 415-417.

6. Lilova MI, Velkovski IG,Topalov IB. Thromboemboliccomplications in children with nephritic syndrome inBulgaria (1974-1996). Pediatr Nephrol 2000; 15: 74-78.

7. Mason PD. Special acute renal problems. In: Davison AM,Cameros JS, Grunfield JP. Oxford Textbook of ClinicalNephrology, 2nd edn. Oxford Medical Publications, NewYork, 2001; p 1631-1632.

8. Koomans HA. Pathophysiology of acute renal failure in

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idiopathic nephritic syndrome. Nephrol Dial Transplant2001; 16: 221-224.

9. Klahr S, Morrissey J. Progression of chronic renal disease.Am J Kidney Dis 2003; 41 (Suppl 1): S3-S7.

10. Prescott WA Jr, Streetman DA. The potential of HMG-CoAreductase inhibitors in pediatric nephrotic syndrome.Ann Pharmacother 2004;38: 2105-1214.