Steroid-sensitive nephrotic syndrome (SSNS)
Francesco Emma
Division of Nephrology and Dialysis
Bambino Gesù Children’s Hos...
“La quinquesimaprima egritudo purroni est inflatio todus corporis purroni”

“The fifty-first disease of children is swelli...
Definitions
Nephrotic Syndrome
- edema
- massive proteinuria (>40 mg/m2/hr)
- hypoalbuminemia (<2.5 g/dl)

Remission
- mar...
Non immune-mediated NS in children
How do we define remission in children?
When should we perform a renal biopsy?

Adapted from Nachman, Jenette and Falk, Brenner & Rector, The kidney, 2008
When should we perform a renal biopsy?

• < 1 year (? …. genetic testing)
• >10-12 years
• If evidence of auto-immune dise...
More definitions…
Steroid Sensitive Nephrotic Syndrome (SSNS)
Response to PDN 60mg/m2/d within 4 weeks

Steroid Resistant ...
More definitions…
Non Relapsing Nephrotic Syndrome (NRNS)
No relapses for > 2 years after the first episode

Infrequently ...
Time to response to PDN

Vivarelli et al, J Pediatr 2010
Time to response to PDN

Nakanishi et al, C JASN 2013
SSNS in adults
Principles of steroid treatment
Relapse

Cumulative
dose of PDN
Principles of steroid treatment
Relapse

Cumulative
dose of PDN
Principles of steroid treatment
Relapse

Cumulative
dose of PDN
Principles of steroid treatment
Relapse

Cumulative
dose of PDN
Risk of relapse by 1-2 years: 2 vs. 3 months of PDN

Cell-mediated

Antibody-mediated
Risk of relapse by 1-2 years: 2 vs. 3 months of PDN
Long vs short PDN treatment
• 46 pts
• ISKDC protocol vs long course protocol (6 months)

Alt, HKJ Ped 2009
Risk of relapse by 1-2 years: 3 vs. 6 months of PDN

Cell-mediated

Antibody-mediated

But higher steroid toxicity!
Benefi...
Relative risk

Relative risk

PDN: dose or duration?

Dose

Duration (months)

Relative risk

Conclusion: duration is more...
PDN tapering or not?

Teeninga et al, JASN 2012
Does treatment of the first episode really matters?

• There is currently little evidence that a specific induction
protoc...
Principles of steroid treatment

Patients need to relapse less than twice/year to have advantage in stopping PDN
Steroid sparing agents in SDNS and FRNS

• Calcineurin inhibitors
• Mofetil mycofenolate
• Levamisole
• Rituximab
• Cyclop...
CSA
Very efficient…
Patient Characteristics

Units

Value

N

Age at CsA initiation

years

6.5 [2.2 - 14.2]

53

Duration...
CSA
But…
• Hypertension
• Requires monitoring of blood levels
• Immune suppression
• Potential renal toxicity
CSA toxicity
PTEC with isometric vacuoles

Striped fibrosis

nodular hyaline arteriosclerosis

nodular hyaline arterioscle...
CSA

Kengne-Wafo et al, Clin J Am Soc Nephrol, 2009
FK506
• Probably more efficient
• Less hypertension
• Other side-effects
• Probably equally toxic for the kidney
MMF

• No renal toxicity
• Immune suppression
• Gastrointestinal and hematological toxicity
• Established teratogenicity
•...
MMF vs CsA

Gellermann et al, JASN 2013
MMF vs CsA

Gellermann et al, JASN 2013
Levamisole
• No published controlled trial (results of 1 trial pending: Elmisol study)
• Numerous small reports
• Probably...
Levamisole: experience in Rome
• 31 FRNS and 24 SDNS
• Number of relapses:
decreased from 3.05 to 1.02 relapses/year
• Cum...
Rituximab
• Numerous reports in the past 5 years + 3 prospective trials
• Clearly efficient, can induce prolonged or long-...
Rituximab

1 year: 60% relapses

Kemper et al Nephrol DialBut: 2012
Transpl

1 year: 70% relapses

Ravani et al Clin J Am ...
Rituximab

Cell-mediated

Antibody-mediated

NEMO study
Should we still use alkylating agents?

Cell-mediated

Antibody-mediated

But, only work well in patients that don’t need ...
Thank you!
Thank you!
Upcoming SlideShare
Loading in …5
×

4-1. Steroid-sensitive nephrotic syndrome. Francesco Emma (eng)

731
-1

Published on

Published in: Health & Medicine
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
731
On Slideshare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
19
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

4-1. Steroid-sensitive nephrotic syndrome. Francesco Emma (eng)

  1. 1. Steroid-sensitive nephrotic syndrome (SSNS) Francesco Emma Division of Nephrology and Dialysis Bambino Gesù Children’s Hospital, IRCCS Rome, Italy
  2. 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. 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. 4. Non immune-mediated NS in children
  5. 5. How do we define remission in children?
  6. 6. When should we perform a renal biopsy? Adapted from Nachman, Jenette and Falk, Brenner & Rector, The kidney, 2008
  7. 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. 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. 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. 10. Time to response to PDN Vivarelli et al, J Pediatr 2010
  11. 11. Time to response to PDN Nakanishi et al, C JASN 2013
  12. 12. SSNS in adults
  13. 13. Principles of steroid treatment Relapse Cumulative dose of PDN
  14. 14. Principles of steroid treatment Relapse Cumulative dose of PDN
  15. 15. Principles of steroid treatment Relapse Cumulative dose of PDN
  16. 16. Principles of steroid treatment Relapse Cumulative dose of PDN
  17. 17. Risk of relapse by 1-2 years: 2 vs. 3 months of PDN Cell-mediated Antibody-mediated
  18. 18. Risk of relapse by 1-2 years: 2 vs. 3 months of PDN
  19. 19. Long vs short PDN treatment • 46 pts • ISKDC protocol vs long course protocol (6 months) Alt, HKJ Ped 2009
  20. 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. 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. 22. PDN tapering or not? Teeninga et al, JASN 2012
  23. 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. 24. Principles of steroid treatment Patients need to relapse less than twice/year to have advantage in stopping PDN
  25. 25. Steroid sparing agents in SDNS and FRNS • Calcineurin inhibitors • Mofetil mycofenolate • Levamisole • Rituximab • Cyclophosphamide
  26. 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. 27. CSA But… • Hypertension • Requires monitoring of blood levels • Immune suppression • Potential renal toxicity
  28. 28. CSA toxicity PTEC with isometric vacuoles Striped fibrosis nodular hyaline arteriosclerosis nodular hyaline arteriosclerosis PathologyOutlines.com
  29. 29. CSA Kengne-Wafo et al, Clin J Am Soc Nephrol, 2009
  30. 30. FK506 • Probably more efficient • Less hypertension • Other side-effects • Probably equally toxic for the kidney
  31. 31. MMF • No renal toxicity • Immune suppression • Gastrointestinal and hematological toxicity • Established teratogenicity • Probably less efficient than calcineurin inhibitors • Variable pharmacokinetics
  32. 32. MMF vs CsA Gellermann et al, JASN 2013
  33. 33. MMF vs CsA Gellermann et al, JASN 2013
  34. 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. 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. 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. 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. 38. Rituximab Cell-mediated Antibody-mediated NEMO study
  39. 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. 40. Thank you! Thank you!
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×