Nephrotic syndrome

consensus statement on nephrotic syndrome

1. CONSENSUS STATEMENT ON NEPHROTIC SYNDROME PRESENTER:DR.SHASIDHAR REDDY

2. DEFINITION Nephrotic syndrome is the clinical manifestation of glomerular diseases associated with heavy ( nephrotic -range) proteinuria .( 40mg/m2/ hr or 50mg/kg/24hr) The triad of clinical findings associated with nephrotic syndrome arising from the large urinary losses of protein are hypoalbuminemia (≤2.5 g/ dL ), edema , and hyperlipidemia (cholesterol >200 mg/ dL ).

3. CLASSIFICATION ETOLOGICAL CLASSIFICATION Primary nephrotic syndrome : (90 %) Disease limited to kidney Not associated with a systemic disease Secondary nephrotic syndrome(10%) – associated with systemic disease such as HSP,SLE, amyloidosis. Children with primary NS are also classified according to their response to steroid therapy as steroid sensitive or steroid-resistant.

4. HISTOLOGICAL CLASSIFICATION: Primary NS or idiopathic nephrotic syndrome includes four histological patterns : 1. Minimal change glomerular disease(MCD) (85%) 2. Diffuse mesangial proliferation (DMP) 3. Focal and segmental glomerulosclerosis (FSGS) 4 . MCD or DMP associated with IgM deposits in the mesangium

5. PATHOPHYSIOLOGY Complex disturbances in immune system Genetic mutation / mutation in proteins Extensive effacement of podocyte foot processes Increased permeability of glomerular basament membrane Massive proteinuria Decreased osmotic pressure and increased hydrostatic pressure in capillaries Hypoalbuminemia

6. Edema Decreased circulatory blood volume - hypovolemia Increased RAS activity Increased sodium and water reabsorption Hemo concentration Increased ADH due to osmoreceptor stimulation Increased water retention Worsening of edema

7. Hypoalbuminemia Increased protien synthesis by liver along with excessive production of lipids and fibrinogen Hyper lipidemia Lipiduria - lipid casts in urine hypercoagulability Urinary loss of coagulation factors

8. INVESTIGATIONS TO CONFIRM DIAGNOSIS: Urine analysis: Nephroticrange proteinuria- Urinary dipstick showing 3 + / 4+ protein Urine protein : creatinine ratio > 2 Proteinuria- 40mg/m2/ hr , 24 hour urine 50mg/kg/24 hr Selective proteinuria seen in Minimal change NS RBC may be present in NS with significant lesions(MPGN,FSGS)

9. Serum proteins - Total proteins decreased Hypoproteinemia (<2.5 gm /dl) AG ratio-reversed Lipid profile - sr.cholesterol - increased

10. TO SCREEN COMPLICATIONS: CBC: Anemia(microcytic hypochromic anemia) Raised platelet count TC,DC(raised in infections) RFT: Serum urea and creatinine -raised in CRF BEFORE STARTING THERAPY: ANA levels Mantoux

11. MANAGEMENT

12. SPECIFIC TREATMENT Treatment of the Initial Episode: Adequate treatment of the initial episode, both in terms of dose and duration of corticosteroids is important. Medication: The standard medication for treatment is prednisolone or prednisone

13. Treatment regimen : Initial episode of nephrotic syndrome treated with prednisolone@ 2mg/kg/day(max of 60mg)in single or divided doses for 6 weeks. f/b 1.5 mg/kg(max of 40 mg)as a single dose for next 6 weeks

14. Remission: Urine albumin nil or trace (or proteinuria <4 mg/m2/h) for 3 consecutive early morning specimens . Relapse: Urine albumin 3+ or 4+ (or proteinuria >40 mg/m2/h) for 3 consecutive early morning specimens,having been in remission previously . Frequent relapses: Two or more relapses in initial six months or more than three 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 8 weeks.

15. Treatment of relapse: The patient should be examined for infections, which should be treated before initiating steroid therapy . Prednisolone is administered at a dose of 2 mg/kg/day (single or divided doses) until urine protein is trace or nil for three consecutive days. Subsequently, prednisolone is given in a single morning dose of 1.5 mg/kg on alternate days for 4 weeks , and then discontinued. The usual duration of treatment for a relapse is thus 5-6 weeks. In case the patient is not in remission despite two weeks treatment with daily prednisolone, the treatment is extended for 2 more weeks. Patients showing no remission despite 4 weeks’ treatment with daily prednisolone should be referred for evaluation .

16. Infrequent relapsers : Patients who have three or less relapses a year and respond promptly to prednisolone are managed using the aforementioned regimen for each relapse. Such children are at a low risk for developing steroid toxicity

17. Frequent relapsers and steroid dependence: Following induction of remission, the dose of prednisolone is tapered gradually to maintain the patient in remission on alternate day dose of 0.5 mg/kg or lower  Alternate day prednisolone may be administered for 9-18 months. A close monitoring of growth and blood pressure, and evaluation for features of steroid toxicity is essential. If the prednisolone threshold, to maintain remission, is higher than 0.5 mg/kg on alternate days, the following immunomodulators are recommended.

18. ( a ) Levamisole - may be administered in a dose of 2 -2.5 mg/kg on alternate days for 12- 24 months Treatment with prednisolone-1.5 mg/kg on alternate days, is continued. The dose of prednisolone is gradually reduced by 0.15-0.25 mg/kg every 4 weeks to a maintenance dose of 0.25 mg/kg, which may be continued for six months. The chief side effect of treatment with levamisole is leukopenia flu-like symptoms and skin rash may occur rarely. The total leukocyte count should be monitored every 4-8 weeks

19. b ) cyclophosphamide (2 mg/kg/day) may be administered along with alternate day prednisolone (1-1.5 mg/kg) for 12 weeks. In view of safer toxicity profile, cyclophosphamide is usually preferred The total leukocyte count should be monitored every 2-3 weeks and treatment is discontinued if leukocyte count falls below 4000/mm3. Treatment with cyclophosphamide may rarely cause alopecia, nausea and vomiting. Treatment with cyclophosphamide may be considered in patients showing: ( i ) significant steroid toxicity, ( ii ) severe relapses with hypovolemia or thrombosis, and ( iii ) poor compliance or follow up.

20. Steroid resistant nephrotic syndrome: Defined as the failure to achieve remission after 8 wk of corticosteroid therapy. Children with steroid-resistant nephrotic syndrome require further evaluation,including a diagnostic kidney biopsy, evaluation of kidney function , and quantitation of urine protein excretion (in addition to urine dipstick testing). Steroid-resistant nephrotic syndrome is usually caused by FSGS (80%), MCNS, or membranoproliferative glomerulonephritis. SRNS and specifically FSGS , is associated with a 50% risk for end-stage kidney disease.

21. Calcineurin inhibitors (cyclosporine or tacrolimus ) are recommended as initial therapy for children with steroid-resistant nephrotic syndrome. Cyclosporine - administered in a dose of 4-5 mg/kg daily for 12-24 months. Therapy is continued with prednisolone in a dose of 1.5 mg/kg on alternate days for 4 weeks, and then tapered gradually Side effects :- hypertension, gum hypertrophy and hirsutism may occur, in which case the dose of cyclosporine may be reduced to 3 mg/kg/day

22. Tacrolimus : Is an alternative agent, administered at a dose of 0.1-0.2 mg/kg daily for 12-24 months . Side effects include hyperglycemia, diarrhea and rarely neurotoxicity ( headache,seizures ). Blood levels of creatinine and glucose should be estimated every 2-3 months.

23. Mycophenolate mofetil ( mmf ): Is given at a dose of 800-1200 mg/m2 along with tapering doses of prednisolone for 12-24 months . side effects include gastrointestinal discomfort, diarrhea and leukopenia . Leukocyte counts should be monitored every 1-2 months treatment is withheld if count falls below 4000/mm3 . The lack of renal,hemodynamic and metabolic toxicity with this agent makes it an attractive alternative to calcineurin inhibitors.

24. The advantages of using these drugs should be balanced against their potential toxicity. Levamisole has a weak steroid sparing effect and is useful in milder cases  Treatment with cyclophosphamide may be considered in patients showing: ( i ) significant steroid toxicity ( ii ) severe relapses with hypovolemia or thrombosis ( iii ) poor compliance or follow up . Cyclosporin is recommended for patients that continue to show steroid dependance or frequent relapses despite a course of levamisole and cyclo-phosphamide .

25. SUPPORTIVE This forms an important aspect of managing children with nephrotic syndrome.

26. DIET A balanced diet adequate in protein and calories is recommended . The child should receive 1.5-2 g/kg of proteins. Patients with persistent proteinuria are prone to mal-nutrition and should receive 2-2.5 g/kg of protein daily.

27. Salt restriction is not necessary in most patients with steroid responsive nephrotic syndrome. Corticosteroids stimulate the appetite, and advice should be given about ensuring physical activity and preventing excessive weight gain.

28. EDEMA Control of edema is an integral part of supportive care. Since treatment with corticosteroids usually leads to diuresis within 5-10 days, diuretics are avoided unless edema is significant . Patients with persistent edema and weight gain of 7-10% are treated with oral frusemide (1-3 mg/kg daily ). Additional treatment with potassium sparing diuretics is not required if frusemide is used at this dose for less than one week.

29. Patients requiring higher doses and prolonged duration of treatment with frusemide should receive potassium sparing diuretics, e.g., spironolactone (2-4 mg/kg daily ). Blood pressure should be monitored frequently. A gradual reduction of edema, over one week, is preferred Edema not responding to the above therapy should be managed in a hospital.

30. For patients with refractory edema, a combination of diuretics and albumin infusion is used. Albumin (20%) is given as an infusion at a dose of 0.5-1 g/kg over 2-4hr, followed by administration of frusemide (1-2 mg/kg IV) While infusion of albumin results in increased urine output, the effect is not sustained and repeated administration might be necessary. Patients receiving albumin should be observed for respiratory distress, hypertension and congestive heart failure.

31. PATIENT AND PARENT EDUCATION A proportion of patients, especially those ( i) with early onset of nephrotic syndrome ( ii) with a frequently relapsing course ( iii) requiring treatment with alkylating agents or Cyclosporine may continue to show relapses beyond adolescence Parental motivation and involvement is essential in the long-term management of these children.

32. They should be provided information about the disease, its expected course and risk of complications and the following are emphasized : (a)Urine examination for protein at home using dipstick , sulfosalicylic acid or boiling test. The examination should be done every morning during a relapse, during intercurrent infections or if there is even mild periorbital puffiness . The frequency of urine examination is reduced , to once or twice a week, before development of significant edema is stressed.

33. ( b ) Maintain a dairy showing results of urine protein examination, medications received and intercurrent infections . ( c ) Ensure normal activity and school attendance ( d ) Since infections are an important cause of morbidity , patients should receive appropriate immunization and other measures for protection .

34. OTHER MEDICATIONS The use of antacids or histamine receptor antagonists is not necessary unless there are symptoms of upper gastrointestinal discomfort . Patients with steroid sensitive nephrotic syndrome do not usually require medications for hyperlipidemia, since lipid normalize following remission.

35. IMMUNIZATION Parents should be advised regarding the need for completing the primary immunization . Administration of some vaccines, e.g ., hepatitis B,MMR or meningococcal vaccines may rarely precipitate a relapse . Patients receiving prednisolone at a dose of 2 mg/kg/day or greater, or total 20 mg/day or greater for more than 14 days are considered immunocompromised , s uch patients should not receive live attenuated vaccines but inactivated or killed vaccines are safe.

36. All children with nephrotic syndrome should receive immunization against pneumococcal infections. Immunization Committee of the IAP recommends 2-4 doses of pneumococcal vaccine for children below 2 yr of age. For previously unimmunized children between 2-5 yr old , a priming dose of the vaccine should be given 8 weeks later. Children older than 5 yr require only a single dose of the vaccine.

37. Revaccination after 5 yr is considered for children (<10-yr-old) with active nephrotic syndrome . Patients in remission and not on immunosuppressive therapy should receive the varicella vaccine . One dose is recommended for children between 12 months and 12 yr of age, and 2 doses separated by an interval of atleast 4 weeks for children 13 yr or older

38. KIDNEY BIOPSY Performed before therapy with calcineurin inhibitors. A biopsy is required to identify the underlying renal disease in certain cases. INDICATIONS • Age of onset <1 year. • Gross hematuria, persistent microscopic hematuria or low serum C3. • Sustained hypertension. • Renal failure not attributable to hypovolemia . • Suspected secondary causes of nephrotic syndrome . • Proteinuria persisting despite 4-weeks of daily corticosteroid therapy. • Before treatment with cyclosporin or tacrolimus

39. COMPLICATIONS Patients with steroid sensitive nephrotic syndrome are at risk for certain complications, early detection of which is necessary . Infections Thrombosis Hypovolemia Hypertension Corticosteroid side effects

40. INFECTIONS Common infections include peritonitis,cellulitis and pneumonia. Viral and bacterial infections may occasionally precipitate relapses in patients previously in remission . Varicella may be a severe illness in patients with nephrotic syndrome receiving corticosteroids or other immunosuppressive drugs.

41. Susceptible patients (those unimmunized or with no history of varicella) who are exposed to a case of chickenpox should therefore receive a single dose of varicella zoster immunoglobulin, within 96 hr of exposure to prevent or lessen the severity of the disease . Since, this preparation is expensive and not easily available, a single dose of intravenous immunoglobulin (400 mg/kg) may be used . Patients who develop varicella should receive intravenous acyclovir (1500 mg/m2/day in 3 doses) or oral acyclovir (80 mg/kg/day in 4 doses) for 7-10 days.

42. The dose of prednisolone should be tapered to 0.5 mg/kg/day or lower during the infection . Patients with nephrotic syndrome who are Mantoux positive but show no evidence of tuberculosis should receive prophylaxis with INH for six months . Those showing evidence of active tuberculosis should receive standard therapy with anti-tubercular drugs

43. INFECTION CLINICAL FEATURES COMMON ORGANISM TREATMENT PERITONITIS Abdominal pain,tenderness,distension,vomitings,ascitic fluid>100leucocytes/mm3 with >50% neutrophils Str.pneumoniae,str.pyogens , e.coli Ceftriaxone/ cefotaxime for 7-10days Ampicillin and aminoglycosides for 7-10 days PNEUMONIA Fever,cough,tachypnea,intercostal retractions,crepitations Str.pneumoniae H.Influenza Staph.aureus Oral : amoxycillin,coamoxyclav,erythromycin Parenteral: ampicillin and aminoglycoside or Cefotaxime /ceftriaxone for 7-10 days.

44. THROMBOSIS Children with nephrotic syndrome are at risk for venous and, rarely, arterial thrombosis. CAUSES: Increased fibrinogen levels Loss of antithrombin - iii,protein - c,protein -s

45. USG, Doppler studies and cranial MRI are useful in confirming the diagnosis . Patients with thrombotic complications require urgent treatment. The treatment includes correction of dehydration and other complications, and use of heparin or low molecular weight heparin (SC) initially, followed by oral anticoagulants on the long term. There is no role for prophylactic treatment with anticoagulants in patients with hypoalbuminemia and edema.

46. HYPERTENSION This may be detected at the onset of nephrotic syndrome or later due to steroid toxicity. Therapy is initiated with ACE inhibitors, calcium channel blockers or β adrenergic antagonists,keeping the blood pressure at less than the 90 th percentile

47. HYPOVOLEMIA This complication can occur due to unsupervised use of diuretics especially if accompanied by septicemia, diarrhea or vomiting. The diagnosis is suggested by moderate to severe abdominal pain, hypotension, tachycardia, cold extremities and poor capillary refill Hematocrit and blood levels of urea and uric acid are elevated. Management consists of rapid infusion of normal saline at a dose of 15-20 mL/kg over 20-30 minutes this is repeated if clinical features of hypovolemia persist. Infusion of 5% albumin (10-15 mL/kg) or 20% albumin (0.5-1 g/kg) may be used in subjects who do not respond despite two boluses of saline.

48. CORTICOSTEROID SIDE EFFECTS Parents should be explained about the side effects of the medications, including increased appetite, impaired growth, behavioral changes, risk of infections, salt and water retention, hypertension and bone demineralization. All patients should be monitored for cushingoid features and blood pressure; six-monthly record of height and weight, and yearly evaluation for cataract should be done. Patients on prolonged (>3 months) treatment with steroids should receive daily supplements of oral calcium (250-500 mg daily) and vitamin D (125-250 IU).

49. REFERENCE NELSON TEXTBOOK OF PEDIATRICS-FIRST SOUTH ASIA EDITION. NAMMALWAR MANUAL OF PEDIATRIC NEPHROLOGY. INDIAN SOCIETY OF PEDIATRIC NEPHROLOGY CONSENSUS STATEMENT ON MANAGEMENT OF NEPHROTIC SYNDROME-2008 INDIAN SOCIETY OF PEDIATRIC NEPHROLOGY CONSENSUS STATEMENT ON MANAGEMENT OF STEROID RESISTANT NEPHROTIC SYNDROME-2009