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4-1. Steroid-sensitive nephrotic syndrome. Francesco Emma (eng)
- 1. Steroid-sensitive nephrotic syndrome (SSNS) Francesco Emma Division of Nephrology and Dialysis Bambino Gesù Children’s Hospital, IRCCS Rome, Italy
- 2. “La quinquesimaprima egritudo purroni est inflatio todus corporis purroni” “The fifty-first disease of children is swelling of their entire body” (1458 circa)
- 3. Definitions Nephrotic Syndrome - edema - massive proteinuria (>40 mg/m2/hr) - hypoalbuminemia (<2.5 g/dl) Remission - marked reduction in proteinuria (<4 mg/m2/hr or neg. dipstick ) - resolution of edema - normalization of serum albumin (≥3.5 g/dl) Relapse - recurrence of massive proteinuria (>40 mg/m2/hr) - positive urine dipstick (≥3+ for 3 days or pos. for 7 days) - edema ISKDC, J Pediatr, 1981 - Niaudet P, Pediatric Nephrology, 2004
- 4. Non immune-mediated NS in children
- 5. How do we define remission in children?
- 6. When should we perform a renal biopsy? Adapted from Nachman, Jenette and Falk, Brenner & Rector, The kidney, 2008
- 7. When should we perform a renal biopsy? • < 1 year (? …. genetic testing) • >10-12 years • If evidence of auto-immune disease • If steroid resistance • If acute renal failure • In general, if there are doubts…
- 8. More definitions… Steroid Sensitive Nephrotic Syndrome (SSNS) Response to PDN 60mg/m2/d within 4 weeks Steroid Resistant Nephrotic Syndrome (SRNS) No response to PDN 60mg/m2/d within 4 weeks MP boluses Multi-Drug Resistant Nephrotic Syndrome (MDRNS) Ill defined, no response to other drugs (CIs, CYP, RTX…) within 6-12 months ISKDC J Pediatr 1981, Niaudet P Pediatric Nephrology, Philadelphia, 2004, Ehrich, Nephrol Dial Transpl 2011
- 9. More definitions… Non Relapsing Nephrotic Syndrome (NRNS) No relapses for > 2 years after the first episode Infrequently Relapsing Nephrotic Syndrome (IRNS) < 2 relapses per 6 months (or < 4 relapses per 12 months) Frequently Relapsing Nephrotic Syndrome (FRNS) > 2 relapses per 6 months (or > 4 relapses per 12 months) Steroid Dependant Nephrotic Syndrome (SDNS) Relapse during steroid therapy or within 15 days of discontinuation ISKDC J Pediatr 1981, Niaudet P Pediatric Nephrology, Philadelphia, 2004, Ehrich, Nephrol Dial Transpl 2011
- 10. Time to response to PDN Vivarelli et al, J Pediatr 2010
- 11. Time to response to PDN Nakanishi et al, C JASN 2013
- 12. SSNS in adults
- 13. Principles of steroid treatment Relapse Cumulative dose of PDN
- 14. Principles of steroid treatment Relapse Cumulative dose of PDN
- 15. Principles of steroid treatment Relapse Cumulative dose of PDN
- 16. Principles of steroid treatment Relapse Cumulative dose of PDN
- 17. Risk of relapse by 1-2 years: 2 vs. 3 months of PDN Cell-mediated Antibody-mediated
- 18. Risk of relapse by 1-2 years: 2 vs. 3 months of PDN
- 19. Long vs short PDN treatment • 46 pts • ISKDC protocol vs long course protocol (6 months) Alt, HKJ Ped 2009
- 20. Risk of relapse by 1-2 years: 3 vs. 6 months of PDN Cell-mediated Antibody-mediated But higher steroid toxicity! Benefits are not well established…
- 21. Relative risk Relative risk PDN: dose or duration? Dose Duration (months) Relative risk Conclusion: duration is more important than the dose ……. Indirect evidence Dose/Duration Hodson, Cochrane 2005
- 22. PDN tapering or not? Teeninga et al, JASN 2012
- 23. Does treatment of the first episode really matters? • There is currently little evidence that a specific induction protocol can modify the long term course of the disease • Toxicity derives primarily from repeated courses of steroids • Understanding the severity of the diseases in a specific child requires to treat all children in the same way at the beginning • Classification of nephrotic syndrome is influenced by the induction regimen
- 24. Principles of steroid treatment Patients need to relapse less than twice/year to have advantage in stopping PDN
- 25. Steroid sparing agents in SDNS and FRNS • Calcineurin inhibitors • Mofetil mycofenolate • Levamisole • Rituximab • Cyclophosphamide
- 26. CSA Very efficient… Patient Characteristics Units Value N Age at CsA initiation years 6.5 [2.2 - 14.2] 53 Duration of NS before CsA years 1.1 [0.4 - 11.2] 53 No of relapses before CsA rel/years 2.3 [1.6 - 5.2] 53 No of relapses on CsA rel/years 0.5 [0.0 - 3.0] 53 CsA dosage mg/kg /d mg/Kg/d 4.2 ±1.2 53 Off PDN after 1 year N (%) 27 (51%) 53 Kengne-Wafo et al, Clin J Am Soc Nephrol, 2009
- 27. CSA But… • Hypertension • Requires monitoring of blood levels • Immune suppression • Potential renal toxicity
- 28. CSA toxicity PTEC with isometric vacuoles Striped fibrosis nodular hyaline arteriosclerosis nodular hyaline arteriosclerosis PathologyOutlines.com
- 29. CSA Kengne-Wafo et al, Clin J Am Soc Nephrol, 2009
- 30. FK506 • Probably more efficient • Less hypertension • Other side-effects • Probably equally toxic for the kidney
- 31. MMF • No renal toxicity • Immune suppression • Gastrointestinal and hematological toxicity • Established teratogenicity • Probably less efficient than calcineurin inhibitors • Variable pharmacokinetics
- 32. MMF vs CsA Gellermann et al, JASN 2013
- 33. MMF vs CsA Gellermann et al, JASN 2013
- 34. Levamisole • No published controlled trial (results of 1 trial pending: Elmisol study) • Numerous small reports • Probably works in mild forms of FRNS • The mode of action unclear (immune-modulation?) • Few side effects (neutropenia, rashes, vasculitis, gastrointestinal) • 2-2.5 mg/kg on alternate days (max 150 mg) • May no longer be available…
- 35. Levamisole: experience in Rome • 31 FRNS and 24 SDNS • Number of relapses: decreased from 3.05 to 1.02 relapses/year • Cumulative PDN dose: decreased from 130 to 78 mg/kg/year • Side effects: - ANCA auto-antibodies: 5 patients (0.8-6.2 years) - leucopenia: 3 patients - vasculitis: 1 patient - arthritis: 2 patients all resolved after discontinuation of the drug Rinaldi S et al. Ped Nephrol 1994 – unpublished data
- 36. Rituximab • Numerous reports in the past 5 years + 3 prospective trials • Clearly efficient, can induce prolonged or long-lasting remission (10-30% of cases) • Allows decreasing or stopping other immune suppressors • Best treatment strategy is not clearly established • Probably more efficient in older children • Optimal dosage not well established (1-4 doses 375 mg/m2) • Few case reports with devastating infections • CD19 depletion generally for 4-8 months (IVIG if infections) • Unclear how many times the treatment can be repeated • Possible loss of efficacy overtime • Expensive Guigonis et al Pediatr Nephrol 2008, Kamei et al Pediatr Nephrol 2009, Prytula et al Pediatr Nephrol 2011, Filler et al Pediatr Nephrol 2010, Gulati et al Clin J Am Soc Nephrol 2010, Kemper et al Pediatr Nephrol 2007, Kemper et al Nephrol Dial Transpl 2012, Ravani et al Clin J Am Soc Nephrol 2011, Ravani et al Kidney Int 2013, NEMO study in preparation
- 37. Rituximab 1 year: 60% relapses Kemper et al Nephrol DialBut: 2012 Transpl 1 year: 70% relapses Ravani et al Clin J Am Soc Nephrol 2011 - Different patients - Different weaning protocols for other drugs - Different type of studies 1 year: 50% relapses 1 year: 80% relapses NEMO study Ravani et al Kidney Int 2013
- 39. Should we still use alkylating agents? Cell-mediated Antibody-mediated But, only work well in patients that don’t need them… Kemer et al, Pediatr Nephrol 2000 - Zaguri et al, Pediatr Nephrol 2011 Baudoin et al, Pediatr Nephrol 2012 - Bagga et al, Am J Kidney Dis 2003