Steroid-Dependent Nephrotic Syndrome

Nicola Sumorok January 10, 2012

Idiopathic Nephrotic Syndrome

Nephrotic syndrome without known etiology

Heavy Proteinuria > 3.5 g/d in adults or > 1.0 g/m in children Hypoalbuminemia < 3.0 g/dL in adults or < 2.5 g/dL in children Edema Hypercholesterolemia

The three leading histological variants associated with INS are:

Minimal change disease (MCD) Focal segmental glomerulosclerosis (FSGS) Membranous nephropathy (MGN)

Prolonged nephrotic range proteinuria leads to renal scarring and eventual renal failure

Idiopathic Nephrotic Syndrome

The duration and severity of proteinuria are known to be surrogate markers of the progression of glomerular disease The main factor predicting the prognosis in all the histologic variants of the INS is the response of proteinuria to therapy Therefore the objectives of treatment are:
To lower proteinuria To reduce the frequency of relapses of nephrotic syndrome To protect the kidney and prevent progression to ESRD

Cattran, et al. KI (2007) 72: 1429-1447

Inherited Causes of Nephrotic Syndrome

Autosomal recessive present in childhood
Nephrotic syndrome type I (NPHS1), also called Congenital nephrotic syndrome of the Finnish type (CNF)
Mutation in the gene NPHS1 on chromosome 19 Nephrin, a transmembrane protein expressed in podocytes

Nephrotic syndrome type 2 (NPHS2), also known as corticosteroid-resistant nephrotic syndrome

Mutation in NPHS2 on chromosome 1 Podocin

Isolated diffuse mesangial sclerosis

Mutation in PLCE1 that codes for PLC1

Treatment of Idiopathic Nephrotic Syndrome

First line = Corticosteroids Second line agents:
Calcineurin inhibitors
Cyclosporine Tacrolimus

Alkylating agents
Cyclophosphamide

Levamisole not available in the US Mycophenolate mofetil Rituximab

Corticosteroids

>95% of children with MCD achieve complete remission of proteinuria after 8 week course of steroids 50-60% remission rate in adults More than half of all patients who are initially steroid responsive go on to experience relapses of their nephrotic syndrome Frequent relapsers (> 2 episodes in 6 months) are at greater risk of becoming steroid dependent Subsequent prolonged therapy with steroids is undesireable due to the potential side effects, therefore alternative therapies are required in these patients

Cyclophosphamide

Randomized trial of 30 children with steroid-sensitive frequently relapsing nephrotic syndrome After achieving complete remission with Prednisolone, patients were randomized to two groups:
Cyclophosphamide 3mg/kg/day x 8 weeks plus maintenance Prednisolone followed by steroid taper Prednisolone taper alone

Barratt, et al. Lancet (1970) 479-482

Barratt, et al. Lancet (1970) 479-482

Long-term follow-up after treatment with Cyclophosphamide

Retrospective study of 143 children with frequently-relapsing or steroid dependent nephrotic syndrome who were treated with Cyclophosphamide Multicenter study, with median of 7.8 yrs follow-up (up to 15 yrs) Objective of the study was to look at long-term effects of cyclophosphamide and to identify parameters that might predict response to treatment Patients included in the study had received Cyclophosphamide 2-2.5 mg/kg/day for 10-12 weeks
Cammas, et al. NDT (2011) 26: 178-184

Cammas, et al. NDT (2011) 26: 178-184

Cyclosporine

20 children (age 3-18) with steroid resistant or steroid dependent nephrotic syndrome
13 were steroid resistant (no response to 60mg/m Prednisone x 8 wks) 7 were steroid dependent (recurrence of proteniuria when the dose of Prednisone was discontinued)

Prior administration of Chlorambucil or Cyclophosphamide Treated with Cyclosporine A for 8 weeks then abruptly discontinued
7mg/kg/day titrated to blood level 100-200ng/ml

Tejani, et al. KI (1988) 33:729-734

Results

14/20 achieved remission (disappearance of edema, resolution of proteinuria for at least 3 days, serum albumin >2.5mg/dl, and normalization of cholesterol) There was reduction in proteinuria in the 6 who did not remit 40% sustained remission at 1 yr after discontinuation of tx:

Tejani, et al. KI (1988) 33:729-734

Meyrier, A. NDT (2003) 18: vi79-vi86

Tacrolimus

Retrospective cohort study of 10 children with steroiddependent nephrotic syndrome who were treated with Tacrolimus 9 pts with minimal change on biopsy, 1 with FSGS All patients had initially responded to steroids, and were then treated with Cyclophosphamide followed by Cyclosporine and then TAC as steroid sparing agents Patients received TAC 0.1 mg/kg/day in two divided doses, with a target trough level of 5-10 g/L Compared the responses to TAC vs Cyclosporine
# of relapses per year Amount of Prednisone required
Sinha, et al. NDT (2006) 21: 1848-1854

 Mean duration of treatment with CYA was 2 yrs and subsequently with TAC was 5 yrs Adverse events: CYA decrease in GFR (4 pts), histological evidence of CNI toxicity (2 pts), and new onset HTN (1 pt) TAC new onset HTN (1 pt), new insulin-dependent diabetes (1 pt) and CNI toxicity (1 pt) Overall, no benefit to using TAC over CYA
Sinha, et al. NDT (2006) 21: 1848-1854

Cyclosporine vs Cyclophosphamide

Prospective, randomized, multicenter, controlled study 73 patients with steroid-sensitive idiopathic NS (frequent relapses or steroid dependence)
11 adults and 55 children (7 lost to follow-up not included)

After inducing remission with Prednisone, patients were randomized to receive:

Cyclophosphamide 2.5mg/kg/day x 8 weeks Cyclosporine 5mg/kg/day (in adults) or 6mg/kg/day (in children) x 9months then tapered off over 3 months

Ponticelli, et al. NDT (1993) 8: 1326-1332

Ponticelli, et al. NDT (1993) 8: 1326-1332

Ponticelli, et al. NDT (1993) 8: 1326-1332

Mycophenolate mofetil
Age 6.8 yrs +/- 2.7 (range 2-15) 56% male, 44% female 6/33 were steroid dependent

Prospective, multicenter, open-label study looking at the efficacy of MMF in children with frequently relapsing nephrotic syndrome 33 patients, all in remission at the time of the study

Received MMF 600 mg/m BID x 6 months; Prednisone was tapered over the first 16 weeks

Hogg, et al. CJASN (2006) 1: 1173-1178

 Adverse events: One pt discontinued MMF because of an ANC of 300/mm One pt was hospitalized for a varicella outbreak while on MMF

Hogg, et al. CJASN (2006) 1: 1173-1178

MMF in adults

7 patients (age range 21-35 yrs) with minimal change disease or FSGS who had multiple relapses of nephrotic syndrome despite treatment with cytotoxic drugs All of the patients were initially steroid responsive; 6 were steroid dependent by the time of the study 6/7 had relapsing disease for >10 yrs, with treatment-related side affects Patients received MMF 1g BID together with Prednisolone
Treatment length ranged from 9 to 21 months

Day, et al. NDT (2002) 17: 2011-2013

 6 patients went into complete remission (urine albumin 0g/24h) and the 7th went in to partial remission (urine albumin <2g/24h) 5 patients were still in complete remission at last follow-up (avg 10 months) No episodes of GI side effects or leukopenia requiring dose reduction
Day, et al. NDT (2002) 17: 2011-2013

Rituximab

Cohort study of 57 patients with steroid-dependent or steroid resistant nephrotic syndrome

33 with SRNS and 24 with SDNS Mean ages of 12.7 (+/- 9.1) and 11.7 (+/- 2.9) years, respectively

All patients had failed treatment with cytotoxic agents in the past, either Cyclophosphamide, Calcineurin inhibitors, or had toxicity with steroids or cytotoxic agents Received Rituximab 375 mg/m weekly x 2 doses (SDNS) or 4 doses (SRNS)
Steroids were tapered over several months Cyclosporine doses significantly reduced

Followed for at least 12 months after treatment

Gulati, et al. CJASN (2010) 5; 2207-2212

Rituximab

Randomized-controlled trial designed to show that Rituximab added to lower doses of Prednisone and Calcineurin inhibitors was noninferior to standard doses 54 children (mean age 11 +/- 4 years) with Idiopathic nephrotic syndrome Included patients who had been on steroids and calcineurin inhibitors for at least 12 months and who had been in remission for at least 6 months Stratified patients by presence of toxicity secondary to steroids or cyclosporine Intervention: Rituximab 375mg/m IV once (in patients without toxicity) or twice (in patients with toxicity)
Prednisone and calcineurin inhibitors were tapered off over 45 days

Control: Standard therapy with steroids and calcineurin inhibitors Primary outcome: Percentage change in proteinuria at 3 months
Ravani, et al. CJASN (2011) 6: 1308-1315

Ravani, et al. CJASN (2011) 6: 1308-1315

Thank you