Nephrotic Syndrome IAP GUIDELINES

Management of NEPHROTIC SYNDROME

1. MANAGEMENT OF STEROID SENSITIVE NEPHROTIC SYNDROME ( RECENT IAP GUIDELINES) DR. MEHBUB UL HAQUE

2. Nephrotic syndrome Nephrotic Syndrome is the clinical manifestation of Primary Glomerular disease that is characterized by 1) Heavy Protenuria / Nephrotic range proteinuria 2) Hypoalbuminemia 3) Hyperlipidemia 4) Edema 2

3. Comparison between definations of 2018 indian socIety of PAEDIATRIC Nephrology ( ispn) guideline , 2021 ispn guidelines and 2021 kidney disease improving global outcomes (kdigo) guidelines

4. Heavy proteinuria is defined as : (1) Unine dipstic 3+ (2) 24 hour urine protein > 3.5 gm (3) urine protein creatinine ratio > 2 Hypoalbuminemia is defined as: (1) < 3.0 gm/dl [ iap] (2) < 2.5 gm/dl [ Nelson] Hyperlipidemia is defined as : (1) serum cholesterol > 200 mg/dl 4

5. ■ NEPHROTIC SYNDROME AFFECTS 1-3 PER 1,00,000 CHILDREN < 16 YEAR AGE ■ WITHOUT TREATMENT THE MORTALITY IS VERY HIGH MOSTLY FROM INFECTIONS ■ FORTUNATELY 80 % OF CHILDREN WITH NEPHROTIC SYNDROME RESPONDS TO CORTICOSTEROID THERAPY 5

6. DEFINITIONS REGARDING NEPHROTIC SYNDROME REMISSION Urine protein nil or trace, Up/Uc < 0.2 For three consecutive days in early morning urine specimen 6

7. RELAPSE Urine protein > 3 + in dipstic, Up/ Uc >2 For three consecutive days in early morning urine specimen in a patient that have been in remission previously 7

8. PARTIAL REMISSION Urine protein 1 + or 2 + in dipstic, Up/Uc > 0.2 < 2 Or 24 hour urine protein 4-40 mg/m²/day, Serum albumin >3g/dl And Absence of Edema 8

9. FREQUENT RELAPSE ISPN 2021 ISPN 2018 KDIGO 2021 1 ) MORE THAN EQUAL TO 2 1 ) MORE THAN EQUAL TO 2 1) MORE THAN EQUAL TO 2 RELAPSE IN FIRST 6 MONTH RELAPSE IN FIRST 6 MONTH RELAPSE IN 6 MONTH AFTER INITIAL THERAPY AFTER INITIAL THERAPY 2) MORE THAN EQUAL TO 4 2 ) MORE THAN EQUAL TO 3 2) MORE THAN EQUAL TO 4 RELAPSE IN 1 YEARS RELAPSE IN ANY 6 MONTH RELAPSE IN 1 YEAR 3 ) MORE THAN EQUAL TO 4 RELAPSE IN 1 YEAR 9

10. Difficult to treat steroid sensitive disease TWO COMPONENTS ARE INCLUDED IN THIS CATEGORY 1) FREQUENT RELAPSE OR SIGNIFICANT STEROID TOXICITY WITH IN FREQUENT RELAPSE 2) FALIURE OF > 2 STEROID SPARING AGENTS ( INCLUDING LEVAMISOLE , CYCLOPHOSPHAMIDE , MYCOPHENOLATE MOFETIL 10

11. STEROID DEPENDENCY Two consecutive relapse when on alternate day steroid therapy Or Within 14 days of discontinuation of the therapy 11

12. STEROID RESISTANCE ISPN 2021 ISPN 2018 KDIGO 2021 LACK OF COMPLETE LAKE OF COMPLETE LACK OF COMPLETE REMISSION DESPITE REMISSION DESPITE REMISSION DESPITE OF DAILY THERAPY OF DAILY THERAPY OF DAILY THERAPY WITH PREDNISONE WITH PREDNISONE WITH PREDNISONE FOR 6 WEEKS FOR 4 WEEKS FOR 4 WEEKS 12

13. Treatment of initial episode OF NEPHROTic SYNDROME

14. GOAL : 1) To confirm diagnosis 2) To rule out any secondary cause 3) To screen for complications 14 INVESTIGATION AT THE FIRST EPISODE OF NEPHROTIC SYNDROME

15. INVESTIGATION: 1) CBC [ Complete Blood Count ] 2) Blood for Urea , Creatinine , Electrolytes 3) Blood for total Protine , Albumin , and Cholesterol 4) Uninalysis and qualitative estimation of protine by spot Up/ Uc 5) Tuberculin test 15

16. ADDITIONAL INVESTIGATION : INDICATION : 1) GROSS HAEMATURIA OR PERSISTENT MICROSCOPIC HAEMATURIA 2) SUSTAINED HYPERTENSION 3) AKI WITHOUT HYPOVOLEMIA 4) SUSPECTED OTHER SECONDARY CAUSE TEST : 1) COMPLEMENT C3 & C4 2) ANA ( Antinuclear Antibody ) 3) ASO ( Anti Sreptolysin O ) 16

17. INDICATION : 1) HISTORY OF JAUNDICE 2) HISTORY OF ANY OTHER LIVER DISEASE TEST : 1) HBSAg 2) Anti HCV 3) Serum Transaminase 17

18. INDICATION: 1) TUBERCULIN TEST POSITIVE 2) HISTORY OF CAONTACT 3) SUSPECTED LOWER RESPIRATORY TRACT INFECTION TEST : CHEST RADIOGRAPHY 18

19. ROLE OF KIDNEY BIOPSY IN TREATMENT OF SSSS ○ The large majority of patients with SSSS show minimal change disease and less commonly FSGN or Mayeloproliferative GN . ○ So the kidney biopsy is not routinely required in children with idiopathic nephrotic syndrome. ○ Patient with frequent relapse also do not require kidney biopsy before initiating therapy with steroid sparing agents like Levamisole , Cyclo- phosphamide , Mycophentolate mofetil or Rituximab . The only exception is Calcineurin inhibitors ( CNI ) 19

20. 2o INDICATIONS FOR KIDNEY BIOPSY 1) Age of onset is more than 12 years 2) Gross Haematuria 3) Persistent Microscopic Haematuria ( > 5 RBC / HPF in 3 or more times ) 4) AKI not attributed to Hypovolemia 5) Systemic Features e.g fever , rash , arthralgia , low compliment C3 6) Initial or late corticosteroid resistance 7) Prolonged therapy with CNI / Calcineurin Inhibitors ( > 30-36 months ) 20

21. COMPARISON BETWEEN ISPN 2021 , ISPN 2018 AND KDIGO 2021 . GUIDELINES FOR PREDNISONE THERAPY OF INITIAL EPISODE ISPN 2021 ISPN 2028 KDIGO 2021

22. IAP GUIDELINES FOR APPROACH TO TREATMENT OF FIRST EPISODE OF NEPHROTIC SYNDROME

23. ☆ However estimation of body surface area involves complex formulae with variable results and calculation using weight is convenient experts prefer to administer prednisolone based on body surface area because calculation using body weight causes relative underdoosing in young children 23

24. ☆☆ There is no evidence to support therapy with preparation other than prednisolone or its active metabolite Use of Defzacort , Betamethasone , Dexamethasone or Methylprednisolone is nor recommended ☆☆☆ Prednisolone always given with food ☆☆☆☆ Use of Antacid , Ranitidine or PPI is not routinely used 24

25. TREATMENT OF RELAPSE OF NEPHROTIC SYNDROME

26. Iap guidelines for APPROACH to the treatment . of relapse of nephrotic syndrome

27. ● A RELAPSE CONVENTIONALLY EMPERICALLY BEEN TREATED AS OUTLINED IN PREVIOUS SLIDE , BUT THE GUIDELINES VARY IN DURATION OF THERAPY. ● REMISSION IS USUALLY ACHIEVED BY 7- 10 DAYS AND DAILY THERAPY RARELY NECESSARY BEYOND 2 WEEKS 27

28. ● IN CASE OF PERSISTENT PROTEINURIA, DAILY THERAPY MAY BE EXTENDED TO MAXIMUM 6 WEEKS ● LACK OF REMISSION DESPITE OF TREATMENT OF 6 WEEKS DAILY PREDNISOLONE THERAPY INDICATES LATE STEROID RESISTANCE 28

29. Treatment of frequenT Relapse of nephrotic syndrome

30. MANAGEMENT OF frequent relapse and steroid dependence ● The guideline Suggests mainly two therapies for the management of frequent Relapse : 1) Long-term corticosteroid therapy 2) Non-corticosteroid therapy

31. LONG TERM CORTICOSTEROID THERAPY IN PATIENTS WITH FREQUENT RELAPSE THE GUIDELINE SUGGESTS . LONG TERM CORTICOSTEROID THERAPY WITH PREDNISOLONE AT TAPERING DOSE OF O.5–0.7 mg/kg ON ALTERNATE DAY FOR 6 MONTH . THE MEDICATION CAN BE TAPPERED TO 0.2~0.3mg/kg 31

32. ☆ Alternate-day Prednisolone therapy during Fever or Respiratory tract infection : Evidence suggests that more than half of relapses in STEROID SENSITIVE NEPHROTIC SYNDROME occurs following upper respiratory tract infection . So the recommendation is start same dose daily therapy for 5-7 days during fever or respiratory tract infection 32

33. NON-CORTICOSTEROID THERAPY ● IN PATIENTS WITH FAILLING ALTERNATE DAY THERAPY WITH PREDNISOLONE RECOMMENDATION IS THERAPY WITH LEVAMISOLE OR MYCOPHENOLATE MOFETIL (MMF) ● IN PATIENTS WITH SIGNIFICANT STEROID TOXICITY HIGH STEROID THRESHOLD OR FALIURE OF LEVAMISOLE THERAPY RECOMMENDATION IS THERAPY WITH CYCLOPHOPHAMIDE OR MYCOPHENOLATE MOFETIL (MMF) 33

34. Features of steroid toxicity 1) HYPOGLYCEMIA ( fasting glucose > 100mg/dl , post-parandial glucose > 140 mg/dl or HbA1c > 5.7 2) OBESITY ( body mass index > equivalent of 27 kg/m² in adults) 3) SHORT STATURE ( hight < 2 SD for age with hight velocity < - 3 SD for age 4) RAISED INTRAOCULAR PRESSURE 5) MYOPAYHY 6) PSYCHOSIS

35. Details of immunosuppressive medications for frequent relapse

36. Difficult to treat steroid sensitive nephrotic syndrome ■ A PROPORTION OF PATIENT WITH STEROID SENSITIVE NEPHROTIC SYNDROME SHOW DISEASE CHARACTERISED BY MULTIPLE RELAPSES DESPITE OF THERAPY WITH STEROID- SPARING AGENTS AND/ OR MEDICATION-ASSOCIATED TOXICITY. DIFFICULT TO TREAT NEPHROTIC SYNDROME IS DEFINED AS PATIENTS WITH i) FREQUENT RELAPSE OR INFREQUENT RELAPSE WITH SIGNIFICANT STEROID TOXICITY ii) FALIURE OF 2 OR MORE STEROID SPARING AGENTS

37. Treatment of difficult to steroid sensitive nephrotic syndrome ■ ■ ■ PATIENTS WITH STEROID SENSITIVE NEPHROTIC SYNDROME USUALLY TREATED WITH CALCINEURIN INHIBITORS ( CNI ) , EITHER CYCLOSPORINE OR TACROLIMUS ■ PATIENTS WHO HAVE FAILED CNI OR HAVE RECEIVED THESE AGENTS FOR PROLONGED DURATION RECOMMENDATION IS TO TREAT WITH RITUXIMAB