steroid-dependent nephrotic syndrome
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Steroid-DependentNephrotic SyndromeNicola SumorokJanuary 10, 2012
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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
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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
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Cattran, et al. KI (2007)
72: 1429-1447
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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
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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 nephroticsyndrome
Frequent relapsers (> 2 episodes in 6 months) are at greater
risk of becoming steroid dependent
Subsequent prolonged therapy with steroids is undesireabledue to the potential side effects, therefore alternative
therapies are required in these patients
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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 maintenancePrednisolone followed by steroid taper
Prednisolone taper alone
Barratt, et al. Lancet(1970) 479-482
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Barratt, et al. Lancet(1970) 479-482
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Cammas, et al. NDT
(2011) 26: 178-184
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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 thedose 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
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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
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Meyrier, A. NDT
(2003) 18: vi79-vi86
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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 thentreated 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
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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
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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 wererandomized 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
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Ponticelli, et al. NDT(1993) 8: 1326-1332
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Ponticelli, et al. NDT
(1993) 8: 1326-1332
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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/m BID x 6 months; Prednisone was
tapered over the first 16 weeks
Hogg, et al. CJASN
(2006) 1: 1173-1178
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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
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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
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6 patients went into complete remission (urine albumin 0g/24h)
and the 7th went in to partial remission (urine albumin
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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 thepast, 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
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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 nephroticsyndrome
Included patients who had been on steroids and calcineurin
inhibitors for at least 12 months and who had been in remission forat least 6 months
Stratified patients by presence of toxicity secondary to steroids orcyclosporine
Intervention: Rituximab 375mg/m IV once (in patients withouttoxicity) 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
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Ravani, et al. CJASN
(2011) 6: 1308-1315
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Thank you