Non-corticosteroid treatment for nephrotic syndrome in children.
BACKGROUND
Eighty to ninety per cent children with steroid sensitive nephrotic syndrome (SSNS) have one or more relapses. About half of these children relapse frequently and are at risk of the adverse effects of corticosteroids. Non-corticosteroid immunosuppressive agents are used to prolong periods of remission in children, who relapse frequently. However these non-corticosteroid agents also have significant potential adverse effects. Currently there is no consensus as to the most appropriate second line agent in children who are steroid sensitive, but who continue to relapse. In this systematic review of randomised controlled trials (RCTs), the benefits and harms of these immunosuppressive agents are evaluated.


OBJECTIVE
To evaluate the benefits and harms of non-corticosteroid immunosuppressive agents in relapsing SSNS in children.


METHODS
Published and unpublished randomised controlled trials were identified from the Cochrane Controlled Trials Register, MEDLINE, EMBASE, reference lists of articles, abstracts from proceedings and contact with known investigators in the area.


METHODS
Randomised or quasi-randomised trials were included if they were carried out in children (aged three months to 18 years) with relapsing SSNS, if they compared non-corticosteroid agents with placebo, prednisone or no treatment, different doses and/ or durations of the same non-corticosteroid agent, different non-corticosteroid agents and if they had outcome data at six months or more.


METHODS
Two reviewers independently reviewed all eligible studies for inclusion, assessed study quality and extracted data. The principle outcome measure was the number of children with and without relapse after six and 12 to 24 months. Secondary outcomes sought were the mean time to next relapse, the mean number of relapses per year and adverse events. A random effects model was used to estimate summary effect measures after testing for heterogeneity. Examination of possible between-study differences due to study quality, different interventions and different populations was attempted by subgroup analysis.


RESULTS
Eighteen trials involving 828 children were identified. Cyclophosphamide (three trials; relative risk (RR) 0.44; 95% confidence intervals (95% CI) 0.26 to 0.73) and chlorambucil (two trials; RR 0.13; 95% CI 0.03 to 0.57) significantly reduced the relapse risk at six to twelve months compared with prednisone alone. In the single chlorambucil versus cyclophosphamide trial, there was no observed difference in relapse risk at two years (RR 1.31; 95% CI 0.80 to 2.13). Cyclosporin was as effective as cyclophosphamide (one trial, RR 1.07; 95% CI 0.48 to 2.35) and chlorambucil (one trial, RR 0.82; 95% CI 0.44 to 1.53) but the effect was not sustained when cyclosporin was ceased. During treatment levamisole (three trials, RR 0.60; 95% CI 0.45 to 0.79) was more effective than steroids alone but the effect was not sustained. Mizoribine (one trial) and azathioprine (two trials) were no more effective than placebo or prednisone alone in maintaining remission.


CONCLUSIONS
Eight weeks courses of cyclophosphamide or chorambucil and prolonged courses of cyclosporin and levamisole reduce the risk of relapse in children with relapsing SSNS compared with corticosteroids alone. Clinically important differences in efficacy among these agents are possible and further comparative trials are still needed. Meanwhile choice between these agents depends on physician and patient preferences related to therapy duration and the type and frequency of complications.
Durkan
A
A
Centre for Kidney Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, Australia, 2145. ElisaH@chw.edu.au
Hodson
E
E
Willis
N
N
Craig
J
J
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002699:Chlorambucil / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007223:Infant; D007978:Levamisole / Q000627:therapeutic use; D009404:Nephrotic Syndrome / Q000188:drug therapy*; D012008:Recurrence
D007166:Immunosuppressive Agents; D002699:Chlorambucil; D007978:Levamisole; D003520:Cyclophosphamide