Efficacy and acceptability of immunosuppressive agents for pediatric frequently-relapsing and steroid-dependent nephrotic syndrome: A network meta-analysis of randomized controlled trials

Abstract

Introduction: A network meta-analysis was conducted to regard the effects of available immunosuppressive medications in pediatric frequently-relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS).

Methods: We reviewed systematically 26 randomized controlled trials (1311 patients) that compared any of the following immunosuppressive agents to placebo/nontreatment (P/NT) or another drug for FRNS/SDNS treatment in children.

Results: The main outcomes were efficacy and acceptability. At the 6-month, cyclophosphamide, chlorambucil, levamisole, and rituximab had better efficacy than P/NT (odds ratio [OR]: 0.09, 0.03, 0.28, and 0.07, respectively); cyclophosphamide was significantly more effective than azathioprine and chlorambucil. At 12 months, cyclophosphamide, chlorambucil, cyclosporine, levamisole, and rituximab had better efficacy than P/NT (0.10, 0.03, 0.10, 0.23, and 0.07, respectively); Chlorambucil were found to be more efficacious than levamisole and MMF (0.12 and 0.09, respectively). At 24 months, cyclophosphamide, chlorambucil, and levamisole had better efficacy than P/NT (0.09, 0.04, and 0.03, respectively); cyclophosphamide had better efficacy than cyclosporine and vincristine (0.17 and 0.39, respectively).

Conclusion: No significant differences in acceptability were found. Our results suggest that cyclophosphamide may be preferred initially in children with FRSN/SDNS, chlorambucil, and rituximab may be acceptable medications for patients with FRSN/SDNS. Long-term follow-up trials focused on gonadal toxicity and limitation of maximum dosage of cyclophosphamide should been carried out.

Figure 1

Study selection process.

Figure 2

Risk of bias graph.

Figure 3

Risk of bias summary.

Figure 4

Network of eligible efficacy and acceptability comparisons. The thickness of the lines reflects the number of studies being compared, and node size reflects the number of randomized individuals.

Figure 5

Efficacy and acceptability of agents at 6-month (A), 12-month (B), and 24-month (C) follow-up time points. Agents are reported in alphabetical order. ORs in the column-defining drug are compared to ORs in the row-defining drug. For efficacy, ORs > 1 favor the column-defining treatment. For acceptability, ORs < 1 favor the first drug in alphabetical order. Significant comparisons are underscored and bolded. AZA = azathioprine, CHL= chlorambucil, CPA = cyclophosphamide, CsA = cyclosporine, LEV = levamisole, MMF = mycophenolate mofetil, PLA= nontreatment/placebo, RTX = rituximab.

Figure 6

Efficacy (real line) and acceptability (dashed line) rankings at 6 months (A), 12 months (B), and 24-month (C) follow-up time points. Ranking reflects the probability of being the best, second best etc agent among the eight tested medications.