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/m² 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 PLCε1

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/m² 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 steroid-dependent 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 μg/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

• 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 • Age 6.8 yrs +/- 2.7 (range 2-15)

• 56% male, 44% female

• 6/33 were steroid dependent

• Received MMF 600 mg/m² BID x 6 months; Prednisone was tapered over the first 16 weeks

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

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

• Adverse events: • One pt discontinued MMF because of

an ANC of 300/mm² • One pt was hospitalized for a varicella

outbreak while on MMF

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/m² 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 non-inferior 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/m² 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