NEPHROTIC_SYNDROME in children presentation and management

Nephrotic syndrome in paediatrics

1. NEPHROTIC SYNDROME

2. DEFINITION Nephrotic syndrome- It is a clinical state characterised by a) Proteinuria - Massive more than 40 mg /m 2 /Hour >50 mg/ kg b) Hypoproteinemia - Albumin less than 2.5 gm /dl - Protein less than 5 gm/dl c) Generalised Edema - Gross d) Hypercholesterolemia- due to Hypoproteinemia (>220 mg/dl), AGE group- 2 -5 years SEX-males >females

3. PATHOGENESIS

4. ETIOLOGY Primary ( Idiopathic nephrotic syndrome ) > 90 % A -With out significant glomerular lesions i ) Minimal change glomerulonephritis - (Commonest) B - With significant glomerular lesions 1) Membranous glomerulonephritis 2) Mesangioproliferative glomerulonephritis 3) Focal segmental glomerulosclerosis

5. SECONDARY 1.Infections- Streptococcal, malaria, leprosy, infectious mononucleosis, HIV Infective endocarditis Hepatitis B Infection 2. Malignancy - Hodgkin's disease - Leukemia - Wilms tumour

6. 3. Drugs-Gold - D- Penicillamine - Nonsteroidal anti inflamatory drugs - Antisnake venom - Anticonvulsants Captopril alpha interferon Probenecid - Rifampicin SECONDARY CONTD…

7. 4. Insect bites- Bee sting 5. Heriditary - ALPORTS syndrome - Congenital nephrotic syndrome. 6. Multisystem disorders-SLE - Polyarthritis nodosa, Vasculitis due to any cause. SECONDARY CONTD…

8. CLASSIFICATION ACCORDING TO AGE 1) Congenital Nephrotic Syndrome (Infantile)-Finnish type. 2) Childhood-Onset between 2-5 years. 3) Adult (Pubertal)

9. CONGENITAL NEPHROTIC SYNDROME Congenital nephrotic syndrome is clinically defined by heavy proteinuria , secondary edema, hypoalbuminemia , and hyperlipidemia in infants presenting in the first three months of life . CLASSIFICATION It can be subdivided into primary and secondary C N S.   1. Primary is more common and has a known inheritance pattern. ( Finnish type ) . Congenital nephrotic syndrome may be associated with malformation syndromes ( Denys brash syndrome ) 2. Secondary is a group of heteregenous disorders, which include congenital infections and diffuse Mesangial sclerosis of unknown etiology. 

10. PRIMARY CONGENITAL NEPHROTIC Syndrome can be of finnish type or non-finnish type. More common and has a known inheritance pattern. It is an autosomal recessive disorder with a poor prognosis and renal transplantation is the only definitive therapy. Secondary causes such as congenital infections like a) Syphilis, b) Cytomegalo virus c) Toxoplasmosis

11. CLINICAL FEATURES Onset is insidious and the progression is gradual. Puffiness of face due to oedema around the eyes. Oedema of the legs . Generalised oedema Ascites , hydrothorax, scrotal oedema in male children Bloated appearance and relative well being of the child. Blood pressure is normal in cases with minimal change nephrotic syndrome. It may be elevated in patients with significant glomerular lesions.

12. INVESTIGATIONS 1. Blood - Hb % 2. Total count 3. Differential count 4. Peripheral smear RBCs will show normocytic normochromic anaemia . 5. Serum proteins-Total - Albumin /globulin ratio will be reversed. -A 2 and beta globulin are elevated  

13. 6. Urine -Macroscopic and microscopic examination Albumin -Heavy proteinuria (3+ or 4+) Proteinuria -mild-150-500 mg,moderate 500mg - 2 gms , Severe > 2Gms). Urine Spot protein creatinine ratio will be > 2 24 hr Urine protein Selective proteinuria – This is the ratio of clearance of the high molecular weight to low molecular weight proteins. A low ratio indicates highly selective proteinuria . Deposits – Hyaline casts granular casts. Urine for RBCs is usually negative. Haematuria may be seen in cases with significant glomerular lesions.

14. 7. Serum cholesterol will be elevated. 8. Serum complement level - C 3 levels will be normal. 9. Electrophoresis (EPP) - IgG levels are decreased and IgM levels are increased. 10. RFT- Blood urea, creatinine will be normal usually. But may be elevated in the presence of severe hypovolemia and decreased renal perfusion.

15. others - Mantoux test - X-Ray chest-Bilateral pleural fluid. - Serum calcium may be decreased. Ultrasonogram of abdomen. Look for free fluid. Investigations for establishing etiology (secondary nephrotic )

16. 12. Renal biopsy-Indications a. Age of onset-(below 1 year and above 10 years) - Age of onset before 1 year. Age of onset after 8 years (Non MCNS are common after this age) b. Patients not responding to steroids c. Persistent haematuria d. Frequent relapse e. Steroid dependent f. Persistently low C 3 g. Hypertension h. Renal failure i. Systemic disease j. Family history of renal disease. k.To evaluate the efficacy of the treatment l. To detect the transformation of MCNS to FSGS.

17. In cases with lesions other than minimalchange glomerulonephritis (MCNS) the renal biopsy helps in establishing histopathological diagnosis. The following changes may be seen. - Focal segmental glomerulosclerosis (FSGN) - Mesangioproliferative - Membrano proliferative glomerulonephritis (MPGN)

18. OTHER INDICATIONS FOR RENAL BIOPSY Kidney biopsy prior to initiation of cyclosporin -A therapy are indicated during the therapy. (Because renal biopsy is a better indicator of renal damage than the GFR estimation, for the nephrotoxicity .

19. TREATMENT 1. Bed rest 2 . Salt restriction. This is important to decrease the edema. No added salt in the diet. Ordinary table salt only. 3. Fluid restriction Total fluid intake should be restricted to the urine output plus insensible fluid loss. It is calculated as 30 ml /kg on young children and 20 ml /kg in older children.)

20. 4) DIET No added salt (500 mg /day) untill oedema subsides. Normal protein intake is recommended. Calories-Decreased in acute phase. Avoid fat intake. 5. Weight monitoring 6. Intake / output monitoring 7. Urine albumin chart 8.Monitoring- Abdominal girth measurement-is needed if ascites is present. Measure the abdominal girth at the level of umblicus daily.

21. 8. Diuretics are indicated if the oedema is severe. Hydrochlorothiazide 4 mg/kg Frusemide 2 mg/kg Intravenous infusion of albumin may be given if the serum albumin is low associated with poor renal perfusion and oliguria . Steroids -should be started if there is no spontaneous remission. Dose- Prednisolone 2 mg/kg for four Weeks. (Then taper the dose, depending on the response to the treatment.) If proteinuria has decreased, give the Prednisolone on alternate days for next 4 weeks. Then slowly taper the dose of steroids

22. APN regimen ( Arbeitsgemeinschaft fur - Padiatrische Nephrologie 1988) Prednisolone 60 mg/m 2 /day (or 2 mg/kg /day) daily x 6 weeks 40 mg/m 2 /day (1.5 mg/kg /day) on alternate days x 6 weeks Modified APN regimen - Tab Prednisolone 2 mg/kg /day for 6 weeks. Followed by 2 mg/kg /day on alternate days for 6 weeks. Relapse Prednisolone 60 mg/m 2 /day till protein free urine 40 mg/m 2 /day 3 days out of 7 days x 6 weeks.

23. b) ISKDC regimen ( International study group on kidney disease in children) Prednisolone-60 mg/ m 2 per day (or 2 mg/kg /day) in 2 to 3 divided doses for 4 weeks. Followed by 40 mg / m 2 day (1.5 mg/kg /day) given daily for 3 consecutive days in a week for 4 consecutive weeks, after which steroid treatment is stopped without tapering. c. Modified ISKDC regimen The second month of treatment is given as 40-mg/m 2 as a single morning dose on alternate days for 4 weeks, rather than on 3 consecutive days of each week.

24. Hypercholesterolemia can be treated by HMG coenzyme reductase inhibitor, which will decrease the cholesterol levels in the blood. ( Lovastatins )

25. Indications for cyclophosphamide therapy 1. Frequent relapse, 2. Steroid resistant, 3. Steroid dependent Dose-2 mg / kg / day Duration 8 weeks for frequent relapse 12 weeks for steroid dependent cases. Contraindications Infection, White blood cell counts- < 5000 / mm3 Chlorambucil Dose- 2-3 mg / kg Duration- 10 weeks

26. Alternate therapy 1.Immunosuppressant Steroids (high doses)-Intravenous methyl prednisolone in a dose of 30 mg/kg /dose as multiple infusions at increasing intervals over a long period for 18 - 20months.

27. 2 . Immunomodulants / Immunostimulants . Levamisole-2-2.5 mg /kg on alternate days for 6 to 36 months. Best results are obtained when this drug is introduced during the steroid induced remission, while tapering of the steroid dose. This is usually seen in cases with relapsing nephrotic syndrome. It is also noted that most relapses are associated with viral infections with lowering of cell-mediated immunity. 3. Anticoagulants - Heparin 4. Other drugs Cyclosporin A / Tacrolimus / Mycophenolate mofetil Is given when the patients have not responded to levamisole and cyclophosphamide .

28. Indications for cyclosporin -A Steroid induced complications Steroid resistant and cyclophosphamide resistant nephrotic syndrome. Drugs which reduce proteinuria 1. Angiotensin converting enzyme inhibitors Captopril or Enalapril can be given. Losartan is an angiotensin II receptor inhibitor used in nephrotic syndrome.

29. 3. Treat associated infections. 4. Blood transfusion or preferably packed cell transfusion can be given in the presence of anemia. 5. Long-term anticoagulants are indicated in renal vein thrombosis. 6.Dialysis is indicated in presence of renal failure. Paracentesis of ascitic fluid or hydrothorax may be indicated if they cause pressure symptoms.

30. Remission Albumin free or Proteinuria trace or nil on 3 consecutive days Serum albumin more than 3.5 gm / dl No edema Relapse Urine albumin > 2 + or Proteinuria more than 40 mg / m 2 on 3 consecutive specimens Frequent relapse More than 2 episodes in 6 months More than 4 episodes in any 12 months Infrequent relapse Less than 3 episodes in 12 months Less than 2 episodes in 6 months

31. Steroid sensitive (steroid responsive) Disappearance of Proteinuria and all clinical and biochemical features with in 8 weeks of starting a standard course of steroid therapy. Steroid Resistance No remission with in 8 weeks of starting a standard course of steroid therapy. Persistent Proteinuria , After Completion of Treatment Steroid Dependent Cases 2 or more consecutive relapses while steroids are tapered or within 2 weeks of stopping them. Relapse after Stopping the Drugs

32. COMPLICATIONS 1) Due to the disease 2) Due to drugs  

33. DUE TO THE DISEASE Infections Due to loss of immunoglobulin Decreased cell mediated immunity Treatment with steroids also renders the patients susceptible to infections. Infections with Streptococcus pneumoniae , gram-negative septicemia, and Varicella are common.   Anemia -Due to loss of transferrin Hypothyroidism -Due to loss IBG. Hypocalcaemia -Due to loss Of Vit D binding globulin and loss Of 1, 25, Dihydoxy cholecalciferol

34. Hypercoagulable States Due to loss of anticoagulation factors like antithrombin III hyperfibrinogenaemia, hyperfibrinogenaemia, impaired, fibrinolysis, reduced activity of protein C and protein Sand enhanced platelet aggregation, Hypovolemia. (Renal Vein Thrombosis, Peripheral Vein Thrombosis, and Cerebral Vein Thrombosis) - Arterial thrombosis occurs in the pulmonary artery. Renal Failure Hypovolemia.This and diuresis may predispose to the development of acute renal failure. Acute Chronic Failure

35. Convulsions Hypocalcaemia Hypertension Renal Failure Hyponatremia Cerebral Vein Thrombosis Pericardial effusion,-Due to fluid retention Hydrothorax-Due to fluid retention. Postural hypotension may be due to hypovolaemia . Accelerated atherosclerosis can occur. Zinc and copper deficiency states due to loss of metal binding proteins.

36. DUE TO DRUGS 1) Steroids Gastritis/Peptic Ulcer, Cataract 2) Cyclophosphamide – Haemmorhagic Cystitis, Bone Marrow Depression, Alopecia 3) Frusemide Hypokalemia , Hyponatremia , Hyperuricemia , Hypercalciuria , Hypocalcemia , Hypovolaemia , Tinnitus, Deafness, Acute Interstitial Nephritis

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