Ssns+srns 2019

Nephrotic Syndrome in Children

1. Nephrotic Syndrome Prof. Imran Iqbal Prof of Paediatrics (2003-2018 ) Multan, Pakistan

2. In the name of ALLAH the most Gracious, the most Merciful

3. Nephrotic Syndrome

4. Nephrotic Syndrome ? Usual Presenting feature is Oedema D/D of Oedema Nephrotic Syndrome Acute Glomerulonephritis Congestive Heart Failure Kwashiorkor Chronic Liver Disease Protein Losing Enteropathy Angioedema

5. OPD Urine Examination Protien = 2 + OR 3 + Urine protein/ creatinine ratio > 2 Nephrotic Syndrome likely

6. Proteinuria Spot urine Trace = 15mg/dl + = 30mg/dl ++ = 100mg/dl +++ = 300mg/dl ++++ = 2000mg/dl Dipstick Boiling P/C ratio

7. Heavy proteinuria ( > 40mg/m 2 /hour or > 50mg/kg/day) Hypoalbuminaemia (< 2.5g/dl) Oedema Hyperlipidaemia (> 220mg/dl) Nephrotic Syndrome

8. Typical Clinical Features Age 2-6 years Boys 70 % Facial Puffiness / marked edema Mild Diarrhea Oliguria Blood Pressure normal or low Anorexia

9. Other PRESENTATIONS of NS GENERALIZED BODY SWELLING- EDEMA, OLIGURIA Abdominal pain Acute kidney injury Infections Shock Thrombo -embolism Hypertension Routine urinalysis

10. EXAMINATION Clinical Assessment of Circulating Volume Toe Temp. Capillary Refill time B.P Pulse Rate, Volume Extent of Edema Infections Systemic Examination Weight, Height, Ideal weight for Height, Surface area

11. COMPLICATIONS Gross edema Hypovolemia Infections – peritonitis, cellulitis , UTI Pneumonia Tuberculosis Arterial / venous thrombosis

12. Atypical Clinical Features Age < 1 year or > 10 years Hematuria Hypertension Azotemia

13. Nephrotic Syndrome in Children Congenital/Infantile NS Primary Secondary Finnish Type DMS Deny –Drash Syndrome MCNS FSGS MN Galloway-Mowat Syndrome Nail-Petella Syndrome Congenital Infections HIV Malaria SLE Childhood NS Secondary SLE HSP Hep B Others Primary (Idiopathic) MCD FSGS DMP MPGN MN

14. Nephrotic Syndrome in Children Primary Nephrotic Syndrome - 95% Minimal Change Disease - 80 %

15. CAUSES OF SECONDARY Nephrotic Syndrome SLE HSP Hepatitis B, C HIV Malaria Lymphoma Drugs (NSAIDS)

16. SLE

17. Secondary NS - Causes Lupus nephritis (LN) HSP nephritis (HSPN) Hepatitis C nephritis - MPGN Hepatitis B nephritis – MN Malaria HIV nephritis Lymphoma Drugs

18. Minimal Change Disease Genetic factors T – cell activation Cytokines – IL 4 & IL 13

19. MCD - pathology

20. Albuminuria

21. PATHOPHYSIOLOGY Under-fill Hypothesis Heavy Albuminuria Hypoalbuminaema Reduced Plasma Oncotic Pressure Continuing Salt & Water Intake OEDEMA Renal Salt & Water retention Hypovolaemia Shift of fluid from plasma to interstitium Reduced GFR Increased proximal tubular salt & water reabsorption Activation of the RAAS Release of ADH Inhibition of atrial natriuretic peptide

22. Labs for Nephrotic Syndrome INITIAL INVESTIGATIONS Urine Exam Serum albumin Urea , Creatinine Lipid profile Na, K, Ca, CBC PT, APTT Subsequent Investigations HBsAg HCV antibody ASO titre USG abdomen Tuberculin test X ray Chest C3 , C4 Anti ds DNA antibodies

23. Management of Nephrotic Syndrome Patient COUNSELING Disease Urine Examination Medicines Complications Immunisations

24. MONITORING Daily home monitoring of proteinuria (PU) by dipsticks or boiling method and keeping diary Follow up every 4 weeks- check weight, BP, PU, edema, side effects of steroids and other medicines Height – every 6 months

25. Immunisations Avoid live vaccines during induction therapy Complete EPI schedule Give Pneumococcal Flu vaccine Varicella vaccine

26. SUPPORTIVE TREATMENT Diet Hypovolemia Diuretics Mucosal protectives Antihypertensives Infections

27. Gross Edema

28. DIURETICS- WHEN TO USE ? Very cautious and judicious use when : Generalized anasarca Massive ascities or pleural effusion causing respiratory difficulty Massive scrotal swelling with imminent skin rupture Concomitant albumin infusions are required to mobilize edema Persistent hypertension

29. DIURETICS-RISKS Intavascular volume depletion Thromboembolism Acute kidney injury Severe electrolyte imbalance

30. Steroid Sensitive Nephrotic Syndrome: 90% Steroid Resistant Nephrotic Syndrome: 10% Primary/ Idiopathic NS

31. Steroid Induction of Remission therapy Prednisolone 60 mg / m2 for 4 wks ( usual remission time 7 – 10 days ) If no remission: Continue same dose for another 4 wks OR MethylPrednisolone IV 30 mg / m2 alternate day for 3 doses

32. Continuation Steroid therapy If remission achieved: Prednisolone 40 mg / m2 alternate day for 4 wks Reduce dose by 5 – 10 mg every 4 weeks Stop treatment by 3 – 6 mo

33. Relapses in Nephrotic Syndrome Relapses 40 – 70 %

34. How to Reduce Relapses 50% of relapses triggered by URTIs. Prolonged Initial steroid therapy Zn supplementation Monteleukast

35. Treatment of Relapse Prednisolone 60 mg / m2 till remission Start AD doses Reduce dose by 5 – 10 mg every 4 weeks

36. Terminology Remission = urine albumin free for 3 days Relapse = urine albumin 3+ for 3 days Frequent Relapser = > 2 relapses in 6 mo or > 3 relapses in 12 mo Steroid Dependant = relapse within 14 days of reducing steroid dose Steroid Resistant = No response to initial steroid therapy in 4 – 8 weeks

37. Types of NEPHROTIC SYNDROME Steroid Sensitive NS (SSNS) Non Relapsing NS (NRNS) Infrequently Relapsing NS (IRNS) Frequently Relapsing NS (FRNS) Steroid Dependant NS (SDNS) Steroid Resistant NS (SRNS) Atypical NS Secondary NS

38. Treatment of Frequent Relapses Prednisolone 10 – 15 mg / m2 in Alternate day doses continued for 1 – 2 years ( upto 0.5 – 1 mg/kg) Cyclophosphamide 2mg /kg for 12 weeks Mycophenolate Mofetil 30 mg / kg / day Cyclosporin Tacrolimus

39. Adverse effects of steroid therapy Infections Cushingoid appearance Emotional problems Hypertension Acid peptic disease Osteoporosis Impaired glucose tolerence Growth retardation

40. Iatrogenic Cushing’s Syndrome

41. MANAGEMENT OF SSNS First Episode of NS Trial of Steroids Response Withdraw Steroids over 6 months Relapse Repeat short Steroid course Infrequent relapse Frequent relapses Intermittent short steroid courses or Steroid dependency No Relapse, discharge Alternate day Steroids Steroids well tolerated Contd. AD Steroids Steroids not well tolerated Consider Alternatives

42. Renal Biopsy Steroid Resistance Age < 1 year >10 years Prolonged mild proteinuria Macroscopic haematuria Marked persistent HTN Persistent renal insufficiency low C3 or C4 Cyclosporine therapy

43. Prognosis of SSNS Relapses decreased after few years In some relapsing patients , Relapses may continue upto 14 – 20 years Renal insufficiency is rare

44. Predictors of prolonged course Early onset of disease Severity of proteinuria Frequent Relapses

45. THANKS

46. S R N S

47. STEROID RESISTANT NS (SRNS) Failure to achieve remission with a standard steroid protocol e.g. Four weeks’ oral prednisolone 60mg/m2/d plus 3 pulses of iv methylprednisolone 30mg/kg /dose given on alternate days Six to 8 weeks’ oral prednisolone 60mg/m2/d

48. SRNS - Treatment Options Cyclosporine ( CsA ) + prednisolone (PDN) Tacrolimus ( Tac ) + PDN Mycophenolate mofetil (MMF) + PDN Combined CsA & MMF + PDN Methylprednisolone (MP) iv pulses + PDN & Cyclophosphamide (CPM) – The Mendoza Protocol Rituximab + PDN ACEIs & ARBs

49. Cyclosporin ( CsA ) French Society of Pediatric Nephrology protocol: CsA 150mg/m2/day BD – 6 months PDN 30mg/m2/day BD – 1 month PDN 30mg/m2/day single morning dose after breakfast – next 5 months Slow taper PDN CsA taper to minimum effective dose to prevent relapse – may continue for 1-2 years

50. CsA - side effects Nephrotoxic ( Monitor RFTs, S/E, trough drug levels, repeat renal biopsy at 1 year ) Hypertrichosis Gum hyperpalsia Hypertension Hypomagnesemia Tremors Hypercholesterolemia

51. Tacrolimus ( Tac ) Tac 0.1-0.2 mg/kg/day BD +PDN Efficacy and side effects profile similar to CsA No cosmetic side effects Other side effects : diarrhea, headache, hyperglycemia

52. Efficacy of Calcineurin Inhibitors

53. Mycophenolate mofetil (MMF) Less effective than CsA MMF 1200mg/m2/day BD plus PDN 60mg/m2/day First taper steroids MMF maintained on minimum effective dose for 1-2 years Side effects : Myelosuppression, abdominal pain, diarrhea – monitor CBC

54. Comparison for SRNS Drugs Complete response Partial response No response Total Tacrolimus 40 (93%) 3 (7%) 43 Cyclosporin 36 (94%) 3 (6%) 38 MMF 18 (86%) 2 (10%) 1 21

55. Methylprednisolone (MP) IV MP pulses 30mg/kg/dose – The Mendoza Protocol Six AD Eight weekly Four fortnightly Eight monthly Four bimonthly

56. MP – side effects Infections Hypertension Cushingoid habitus Acne Hyperglycemia Growth suppression Osteoporosis Gastric ulcers Mood changes Cataract

57. Cyclophosphamide (CPM) Not recommended alone with PDN in SRNS Added to Mendoza protocol if remission not achieved with IVMPP Dose : 2-2.5mg/kg/day OD – 3 months – safe cumulative dose is 168mg/kg Side effects: Leukopenia , alopecia, sterile hemorrhagic cystitis, gonadal toxicity in prepubertal and post pubertal patients, late malignancy

58. Impact of Histopathology On Treatment Outcome Histopathological Lesion Number of patients (%age) Complete Remission Partial Remission No Remission FSGS 28 (36.4%) 12 (15.6%) 02 (2.6%) 12 (15.6%) MesPGN 23 (29.9%) 15 (19.5%) 01 (1.3%) 08 (10.4%) MCD 18 (23.4%) 14 (18.2%) 01 (1.3%) 04 (5.2%) No biopsy done 08 (10.4%) 05 (6.5%) 00 03 (3.9%) Total 77 (100%) 46 (59.7%) 04 (5.2%) 27 (35.1%)

59. International Study of Kidney Disease in Children , The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr . 981;98(4 ):561–4 . (2) Murnaghan K, Vasmant D, Bensman A. Pulse methylprednisolone therapy in severe idiopathic childhood nephrotic syndrome. Acta Paediatr Scand . 1984;73(6 ):733–9 . (3) KDIGO Clinical Practice Guideline for Glomerulonephritis. Kid Intl June 2012; 2(2)

60. NO RESPONSE TRIPLE REGIME ACEIs/ARBs METHYLPREDNISOLONE MMF ( 15 mg/kg/week ) ( 250 – 500 mg/m2/day Max ) Lombel RM, Hodson EM & Gipson DS. Treatment of steroid-resistant nephrotic syndrome in children: new guidelines from KDIGO. Pediatr Nephrol 2013 ; 28(3), 409–414 STOP STEROIDS & CALCINEURIN INHIBITORS X 4-8 weeks x 24 months

61. Thanks...