This document provides definitions and guidelines for treating steroid-sensitive nephrotic syndrome (SSNS) in children. It discusses that SSNS responds well to prednisone treatment within 4 weeks. The optimal duration of prednisone treatment is debated, with some evidence that longer treatment (3-6 months) reduces relapse risk compared to shorter courses, though it increases steroid toxicity risks. For children who frequently relapse or are steroid dependent, calcineurin inhibitors, mycophenolate mofetil, levamisole, and rituximab may be effective steroid-sparing agents, with varying risks and levels of evidence supporting each option. The document outlines guidelines but notes treatment must be tailored to each individual child

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

38. Rituximab
Cell-mediated
Antibody-mediated
NEMO study

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

40. Thank you!
Thank you!