Steroid-sensitive nephrotic syndrome (SSNS)

Francesco Emma

Division of Nephrology and DialysisBambino Gesù Children’s Hospital, IRCCS

Rome, Italy

“La quinquesimaprima egritudo purroni est inflatio todus corporis purroni”

“The fifty-first disease of children is swelling of their entire body” (1458 circa)

De Ægritudinibus InfantiumCornelius Roelans de Mechlinia (1450-1525)

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

Definitions

Non immune-mediated NS in children

How do we define remission in children?

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 disease

• If steroid resistance

• If acute renal failure

• In general, if there are doubts…

When should we perform a renal biopsy?

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

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

More definitions…

Vivarelli et al, J Pediatr 2010

Time to response to PDN

Nakanishi et al, C JASN 2013

Time to response to PDN

SSNS in adults

Principles of steroid treatment

Relapse Cumulativedose of PDN

Principles of steroid treatment

Relapse Cumulativedose of PDN

Principles of steroid treatment

Relapse Cumulativedose of PDN

Principles of steroid treatment

Relapse Cumulativedose of PDN

Cell-mediated Antibody-mediated

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

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

Alt, HKJ Ped 2009

• 46 pts

• ISKDC protocol vs long course protocol (6 months)

Long vs short PDN treatment

Cell-mediated Antibody-mediated

But higher steroid toxicity! Benefits are not well established…

Risk of relapse by 1-2 years: 3 vs. 6 months of PDN

PDN: dose or duration?

Hodson, Cochrane 2005

Dose Duration (months)

Rela

tive

risk

Rela

tive

risk

Dose/Duration

Rela

tive

risk

Indirect evidence

Conclusion: duration is more important than the dose …….

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 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

Principles of steroid treatment

Patients need to relapse less than twice/year to have advantage in stopping PDN

• Calcineurin inhibitors

• Mofetil mycofenolate

• Levamisole

• Rituximab

• Cyclophosphamide

Steroid sparing agents in SDNS and FRNS

Kengne-Wafo et al, Clin J Am Soc Nephrol, 2009

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

Very efficient…

CSA

• Hypertension• Requires monitoring of blood levels• Immune suppression• Potential renal toxicity

CSA

But…

CSA toxicity

PathologyOutlines.com

PTEC with isometric vacuoles Striped fibrosis

nodular hyaline arteriosclerosis nodular hyaline arteriosclerosis

CSA

Kengne-Wafo et al, Clin J Am Soc Nephrol, 2009

• Probably more efficient• Less hypertension• Other side-effects• Probably equally toxic for the kidney

FK506

• No renal toxicity

• Immune suppression

• Gastrointestinal and hematological toxicity

• Established teratogenicity

• Probably less efficient than calcineurin inhibitors

• Variable pharmacokinetics

MMF

MMF vs CsA

Gellermann et al, JASN 2013

MMF vs CsA

Gellermann et al, JASN 2013

• 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…

Levamisole

Rinaldi S et al. Ped Nephrol 1994 – unpublished data

• 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

Levamisole: experience in Rome

• 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

Rituximab

Ravani et al Clin J Am Soc Nephrol 2011

NEMO study

Kemper et al Nephrol Dial Transpl 2012

1 year: 70% relapses

1 year: 50% relapses

1 year: 60% relapses

Rituximab

Ravani et al Kidney Int 2013

But:- Different patients - Different weaning protocols for other drugs- Different type of studies

1 year: 80% relapses

NEMO study

Cell-mediated Antibody-mediated

Rituximab

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 2011Baudoin et al, Pediatr Nephrol 2012 - Bagga et al, Am J Kidney Dis 2003

Should we still use alkylating agents?

Thank you!Thank you!