Steroid-Dependent Nephrotic Syndrome
Steroid-Dependent Nephrotic Syndrome
Steroid-Dependent Nephrotic Syndrome
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<strong>Steroid</strong>-<strong>Dependent</strong><br />
<strong>Nephrotic</strong> <strong>Syndrome</strong><br />
Nicola Sumorok<br />
January 10, 2012
Idiopathic <strong>Nephrotic</strong> <strong>Syndrome</strong><br />
• <strong>Nephrotic</strong> syndrome without known etiology<br />
• Heavy Proteinuria > 3.5 g/d in adults or > 1.0 g/m² in children<br />
• Hypoalbuminemia < 3.0 g/dL in adults or < 2.5 g/dL in children<br />
• Edema<br />
• Hypercholesterolemia<br />
• The three leading histological variants associated with INS are:<br />
• Minimal change disease (MCD)<br />
• Focal segmental glomerulosclerosis (FSGS)<br />
• Membranous nephropathy (MGN)<br />
• Prolonged nephrotic range proteinuria leads to renal scarring<br />
and eventual renal failure
Idiopathic <strong>Nephrotic</strong> <strong>Syndrome</strong><br />
• The duration and severity of proteinuria are known to be<br />
surrogate markers of the progression of glomerular disease<br />
• The main factor predicting the prognosis in all the histologic<br />
variants of the INS is the response of proteinuria to therapy<br />
• Therefore the objectives of treatment are:<br />
• To lower proteinuria<br />
• To reduce the frequency of relapses of nephrotic syndrome<br />
• To protect the kidney and prevent progression to ESRD
Cattran, et al. KI (2007)<br />
72: 1429-1447
Inherited Causes of <strong>Nephrotic</strong> <strong>Syndrome</strong><br />
• Autosomal recessive – present in childhood<br />
• <strong>Nephrotic</strong> syndrome type I (NPHS1), also called Congenital<br />
nephrotic syndrome of the Finnish type (CNF)<br />
• Mutation in the gene NPHS1 on chromosome 19<br />
• Nephrin, a transmembrane protein expressed in podocytes<br />
• <strong>Nephrotic</strong> syndrome type 2 (NPHS2), also known as<br />
corticosteroid-resistant nephrotic syndrome<br />
• Mutation in NPHS2 on chromosome 1<br />
• Podocin<br />
• Isolated diffuse mesangial sclerosis<br />
• Mutation in PLCE1 that codes for PLCε1
Treatment of Idiopathic <strong>Nephrotic</strong> <strong>Syndrome</strong><br />
• First line = Corticosteroids<br />
• Second line agents:<br />
• Calcineurin inhibitors<br />
• Cyclosporine<br />
• Tacrolimus<br />
• Alkylating agents<br />
• Cyclophosphamide<br />
• Levamisole – not available in the US<br />
• Mycophenolate mofetil<br />
• Rituximab
Corticosteroids<br />
• >95% of children with MCD achieve complete remission of<br />
proteinuria after 8 week course of steroids<br />
• 50-60% remission rate in adults<br />
• More than half of all patients who are initially steroid<br />
responsive go on to experience relapses of their nephrotic<br />
syndrome<br />
• Frequent relapsers (> 2 episodes in 6 months) are at greater<br />
risk of becoming steroid dependent<br />
• Subsequent prolonged therapy with steroids is undesireable<br />
due to the potential side effects, therefore alternative<br />
therapies are required in these patients
Cyclophosphamide<br />
• Randomized trial of 30 children with steroid-sensitive<br />
frequently relapsing nephrotic syndrome<br />
• After achieving complete remission with Prednisolone,<br />
patients were randomized to two groups:<br />
• Cyclophosphamide 3mg/kg/day x 8 weeks plus maintenance<br />
Prednisolone followed by steroid taper<br />
• Prednisolone taper alone<br />
Barratt, et al. Lancet<br />
(1970) 479-482
Barratt, et al. Lancet<br />
(1970) 479-482
Long-term follow-up after treatment with<br />
Cyclophosphamide<br />
• Retrospective study of 143 children with frequently-relapsing<br />
or steroid dependent nephrotic syndrome who were treated<br />
with Cyclophosphamide<br />
• Multicenter study, with median of 7.8 yrs follow-up (up to 15<br />
yrs)<br />
• Objective of the study was to look at long-term effects of<br />
cyclophosphamide and to identify parameters that might<br />
predict response to treatment<br />
• Patients included in the study had received Cyclophosphamide<br />
2-2.5 mg/kg/day for 10-12 weeks<br />
Cammas, et al. NDT<br />
(2011) 26: 178-184
Cammas, et al. NDT<br />
(2011) 26: 178-184
Cyclosporine<br />
• 20 children (age 3-18) with steroid resistant or steroid<br />
dependent nephrotic syndrome<br />
• 13 were steroid resistant (no response to 60mg/m² Prednisone x<br />
8 wks)<br />
• 7 were steroid dependent (recurrence of proteniuria when the<br />
dose of Prednisone was discontinued)<br />
• Prior administration of Chlorambucil or Cyclophosphamide<br />
• Treated with Cyclosporine A for 8 weeks then abruptly<br />
discontinued<br />
• 7mg/kg/day titrated to blood level 100-200ng/ml<br />
Tejani, et al. KI<br />
(1988) 33:729-734
Results<br />
• 14/20 achieved remission (disappearance of edema,<br />
resolution of proteinuria for at least 3 days, serum albumin<br />
>2.5mg/dl, and normalization of cholesterol)<br />
• There was reduction in proteinuria in the 6 who did not remit<br />
• 40% sustained remission at 1 yr after discontinuation of tx:<br />
Tejani, et al. KI<br />
(1988) 33:729-734
Meyrier, A. NDT<br />
(2003) 18: vi79-vi86
Tacrolimus<br />
• Retrospective cohort study of 10 children with steroiddependent<br />
nephrotic syndrome who were treated with<br />
Tacrolimus<br />
• 9 pts with minimal change on biopsy, 1 with FSGS<br />
• All patients had initially responded to steroids, and were then<br />
treated with Cyclophosphamide followed by Cyclosporine and<br />
then TAC as steroid sparing agents<br />
• Patients received TAC 0.1 mg/kg/day in two divided doses,<br />
with a target trough level of 5-10 μg/L<br />
• Compared the responses to TAC vs Cyclosporine<br />
• # of relapses per year<br />
• Amount of Prednisone required<br />
Sinha, et al. NDT (2006)<br />
21: 1848-1854
• Mean duration of treatment with CYA was 2 yrs and subsequently with<br />
TAC was 5 yrs<br />
• Adverse events:<br />
• CYA – decrease in GFR (4 pts), histological evidence of CNI toxicity<br />
(2 pts), and new onset HTN (1 pt)<br />
• TAC – new onset HTN (1 pt), new insulin-dependent diabetes (1 pt)<br />
and CNI toxicity (1 pt)<br />
• Overall, no benefit to using TAC over CYA<br />
Sinha, et al. NDT (2006)<br />
21: 1848-1854
Cyclosporine vs Cyclophosphamide<br />
• Prospective, randomized, multicenter, controlled study<br />
• 73 patients with steroid-sensitive idiopathic NS (frequent<br />
relapses or steroid dependence)<br />
• 11 adults and 55 children (7 lost to follow-up not included)<br />
• After inducing remission with Prednisone, patients were<br />
randomized to receive:<br />
• Cyclophosphamide 2.5mg/kg/day x 8 weeks<br />
• Cyclosporine 5mg/kg/day (in adults) or 6mg/kg/day (in children)<br />
x 9months then tapered off over 3 months<br />
Ponticelli, et al. NDT<br />
(1993) 8: 1326-1332
Ponticelli, et al. NDT<br />
(1993) 8: 1326-1332
Ponticelli, et al. NDT<br />
(1993) 8: 1326-1332
Mycophenolate mofetil<br />
• Prospective, multicenter, open-label study looking at the<br />
efficacy of MMF in children with frequently relapsing<br />
nephrotic syndrome<br />
• 33 patients, all in remission at the time of the study<br />
• Age 6.8 yrs +/- 2.7 (range 2-15)<br />
• 56% male, 44% female<br />
• 6/33 were steroid dependent<br />
• Received MMF 600 mg/m² BID x 6 months; Prednisone was<br />
tapered over the first 16 weeks<br />
Hogg, et al. CJASN<br />
(2006) 1: 1173-1178
• Adverse events:<br />
• One pt discontinued MMF because of<br />
an ANC of 300/mm²<br />
• One pt was hospitalized for a varicella<br />
outbreak while on MMF<br />
Hogg, et al. CJASN<br />
(2006) 1: 1173-1178
MMF in adults<br />
• 7 patients (age range 21-35 yrs) with minimal change disease<br />
or FSGS who had multiple relapses of nephrotic syndrome<br />
despite treatment with cytotoxic drugs<br />
• All of the patients were initially steroid responsive; 6 were<br />
steroid dependent by the time of the study<br />
• 6/7 had relapsing disease for >10 yrs, with treatment-related<br />
side affects<br />
• Patients received MMF 1g BID together with Prednisolone<br />
• Treatment length ranged from 9 to 21 months<br />
Day, et al. NDT (2002)<br />
17: 2011-2013
• 6 patients went into complete remission (urine albumin 0g/24h)<br />
and the 7 th went in to partial remission (urine albumin
Rituximab<br />
• Cohort study of 57 patients with steroid-dependent or steroid<br />
resistant nephrotic syndrome<br />
• 33 with SRNS and 24 with SDNS<br />
• Mean ages of 12.7 (+/- 9.1) and 11.7 (+/- 2.9) years, respectively<br />
• All patients had failed treatment with cytotoxic agents in the<br />
past, either Cyclophosphamide, Calcineurin inhibitors, or had<br />
toxicity with steroids or cytotoxic agents<br />
• Received Rituximab 375 mg/m² weekly x 2 doses (SDNS) or 4<br />
doses (SRNS)<br />
• <strong>Steroid</strong>s were tapered over several months<br />
• Cyclosporine doses significantly reduced<br />
• Followed for at least 12 months after treatment<br />
Gulati, et al. CJASN<br />
(2010) 5; 2207-2212
Rituximab<br />
• Randomized-controlled trial designed to show that Rituximab added<br />
to lower doses of Prednisone and Calcineurin inhibitors was noninferior<br />
to standard doses<br />
• 54 children (mean age 11 +/- 4 years) with Idiopathic nephrotic<br />
syndrome<br />
• Included patients who had been on steroids and calcineurin<br />
inhibitors for at least 12 months and who had been in remission for<br />
at least 6 months<br />
• Stratified patients by presence of toxicity secondary to steroids or<br />
cyclosporine<br />
• Intervention: Rituximab 375mg/m² IV once (in patients without<br />
toxicity) or twice (in patients with toxicity)<br />
• Prednisone and calcineurin inhibitors were tapered off over 45 days<br />
• Control: Standard therapy with steroids and calcineurin inhibitors<br />
• Primary outcome: Percentage change in proteinuria at 3 months<br />
Ravani, et al. CJASN<br />
(2011) 6: 1308-1315
Ravani, et al. CJASN<br />
(2011) 6: 1308-1315
Thank you