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
• Adverse events:
• One pt discontinued MMF because of
an ANC of 300/mm²
• One pt was hospitalized for a varicella
Hogg, et al. CJASN
outbreak while on MMF
(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/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