Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children.

BACKGROUND: About 80% to 90% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, around half relapse frequently, and are at risk of adverse effects from corticosteroids. Non-corticosteroid immunosuppressive medications are used to prolong periods of remission in these children; however, these medications have significant potential adverse effects. Currently, there is no consensus about the most appropriate second line agent in children who are steroid sensitive, but who continue to relapse. This is the third update of a review first published in 2001 and updated in 2005 and 2008.

OBJECTIVES: To evaluate the benefits and harms of non-corticosteroid immunosuppressive medications in relapsing SSNS in children.

SEARCH METHODS: For this update we searched the Cochrane Renal Group's Specialised Register to June 2013.

SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs were included if they compared non-corticosteroid immunosuppressive medications with placebo, prednisone or no treatment, different non-corticosteroid immunosuppressive medications and different doses, durations or routes of administration of the same non-corticosteroid immunosuppressive medication.

DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias of the included studies and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).

MAIN RESULTS: We identified 32 studies (1443 children) of which one study is still ongoing. In the 31 studies with data, risk of bias assessment indicated that 11 (37%) and 16 (53%) studies were at low risk of bias for sequence generation and allocation concealment respectively. Six (29%) studies were at low risk of performance and detection bias. Twenty seven (87%) and 19 (60%) studies were at low risk of incomplete and selective reporting respectively. Alkylating agents (cyclophosphamide and chlorambucil) significantly reduced the risk of relapse at six to 12 months (RR 0.43, 95% CI 0.31 to 0.60) and 12 to 24 months (RR 0.20, 95% CI 0.09 to 0.46) compared with prednisone alone. There was no significant difference in relapse risk at two years between chlorambucil and cyclophosphamide (RR 1.31, 95% CI 0.80 to 2.13). There was no significant 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) at the end of therapy while levamisole (RR 0.47, 95% CI 0.24 to 0.89) was more effective than steroids alone. However the effects of cyclosporin and levamisole were not sustained once treatment was stopped. In one small study cyclosporin significantly reduced the relapse rate compared with mycophenolate mofetil (MD 0.75, 95% CI 0.01 to 1.49). Limited data from a cross-over study suggested that cyclosporin was more effective than mycophenolate mofetil in maintaining remission. In steroid- and cyclosporin-dependent disease, rituximab significantly reduced the risk of relapse at three months compared with conventional therapy. 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. Limited data indicate that mycophenolate mofetil and rituximab are valuable additional medications for relapsing SSNS. However clinically important differences in efficacy are possible and further comparative studies are still needed.