E M Hodson1, N S Willis, J C Craig. 1. Children's Hospital at Westmead, Centre for Kidney Research, Locked Bag 4001, Westmead, NSW, Australia, 2145. Elisah@chw.edu.au
Abstract
BACKGROUND: Eighty to 90% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. About half relapse frequently and are at risk of the adverse effects of corticosteroids. Non-corticosteroid immunosuppressive agents are used to prolong periods of remission in these children, however these agents 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. OBJECTIVES: To evaluate the benefits and harms of non-corticosteroid immunosuppressive agents in relapsing SSNS in children. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, reference lists, conference abstracts and contact with known investigators. Search date: September 2007 SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs were included 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. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as relative risk (RR) with 95% confidence intervals (CI). MAIN RESULTS: We identified 26 studies (1173 children). Cyclophosphamide (RR 0.44, 95% CI 0.26 to 0.73) and chlorambucil (RR 0.15, 95% CI 0.02 to 0.95) significantly reduced the relapse risk at six to twelve months compared with prednisone alone. There was no difference in relapse risk at two years between chlorambucil and cyclophosphamide (RR 1.31, 95% CI 0.80 to 2.13). There was no difference at one year between intravenous and oral cyclophosphamide (RR 0.99, 95% CI 0.76 to 1.29). Cyclosporin was as effective as cyclophosphamide (RR 1.07, 95% CI 0.48 to 2.35) and chlorambucil (RR 0.82, 95% CI 0.44 to 1.53) and levamisole (RR 0.43, 95% CI 0.27 to 0.68) was more effective than steroids alone but the effects were not sustained once treatment was stopped. There was no difference in the risk for relapse between mycophenolate mofetil and cyclosporin (RR 5.00, 95% CI 0.68 to 36.66) but CI were large. Mizoribine and azathioprine were no more effective than placebo or prednisone alone in maintaining remission. AUTHORS' CONCLUSIONS: Eight week courses of cyclophosphamide or chlorambucil 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 are possible and further comparative studies are still needed.
BACKGROUND: Eighty to 90% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. About half relapse frequently and are at risk of the adverse effects of corticosteroids. Non-corticosteroid immunosuppressive agents are used to prolong periods of remission in these children, however these agents 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. OBJECTIVES: To evaluate the benefits and harms of non-corticosteroid immunosuppressive agents in relapsing SSNS in children. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, reference lists, conference abstracts and contact with known investigators. Search date: September 2007 SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs were included 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. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as relative risk (RR) with 95% confidence intervals (CI). MAIN RESULTS: We identified 26 studies (1173 children). Cyclophosphamide (RR 0.44, 95% CI 0.26 to 0.73) and chlorambucil (RR 0.15, 95% CI 0.02 to 0.95) significantly reduced the relapse risk at six to twelve months compared with prednisone alone. There was no difference in relapse risk at two years between chlorambucil and cyclophosphamide (RR 1.31, 95% CI 0.80 to 2.13). There was no difference at one year between intravenous and oral cyclophosphamide (RR 0.99, 95% CI 0.76 to 1.29). Cyclosporin was as effective as cyclophosphamide (RR 1.07, 95% CI 0.48 to 2.35) and chlorambucil (RR 0.82, 95% CI 0.44 to 1.53) and levamisole (RR 0.43, 95% CI 0.27 to 0.68) was more effective than steroids alone but the effects were not sustained once treatment was stopped. There was no difference in the risk for relapse between mycophenolate mofetil and cyclosporin (RR 5.00, 95% CI 0.68 to 36.66) but CI were large. Mizoribine and azathioprine were no more effective than placebo or prednisone alone in maintaining remission. AUTHORS' CONCLUSIONS: Eight week courses of cyclophosphamide or chlorambucil 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 are possible and further comparative studies are still needed.