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

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Steroid-Dependent Nephrotic Syndrome