Age at onset and cumulative initial prednisolone dose predict frequent relapses in steroid-sensitive nephrotic syndrome: an individual participant data systematic review and meta-analysis of placebo-controlled RCTs.

backgroundBased on evidence from high-quality RCTs, current guidelines recommend that the initial episode of childhood-onset steroid-sensitive nephrotic syndrome be treated with prednisolone for 8-12 weeks. However, the relative impact of extended versus standard prednisolone therapy on outcomes requires evaluation alongside patient characteristics known to affect disease course.

objectivesTo examine whether extending the duration of therapy for the initial episode of childhood-onset nephrotic syndrome reduces the risk of first and frequent relapses and annual relapse rate and whether sex, age at onset, ethnicity, time to remission, and cumulative prednisolone dose modify, confound, or independently influence these measures. DATA SOURCES: PubMed, Embase, and Cochrane Central Register. STUDY ELIGIBILITY CRITERIA: Placebo-controlled RCTs, published during 1980-2024, that compared extended (> 12 weeks) to standard (8-12 weeks) prednisolone therapy in pediatric patients at onset of steroid-sensitive nephrotic syndrome and for which individual participant data (IPD) was made available. PARTICIPANTS AND

interventionsPatients, 1-18 years old, treated with predniso(lo)ne for the first episode of steroid-sensitive nephrotic syndrome. STUDY APPRAISAL AND SYNTHESIS

methodsCochrane Risk of Bias 2 tool; two- and one-stage IPD analyses.

methodsThis systematic review and IPD meta-analysis examined the time to first relapse and frequent relapses (estimated as hazard ratios, HR (95% CI)) and annual relapse rate following extended or standard therapy with prednisolone in pediatric patients with the initial episode of steroid-sensitive nephrotic syndrome. One-stage and two-stage IPD analyses examined sex, age, ethnicity, and time to remission as effect modifiers, confounders, and covariates of treatment effect.

resultsThe IPD meta-analyses included 529 of 568 patients from three RCTs; 49% and 51% participants received extended and standard therapy, respectively. On two-stage meta-analysis, compared to standard therapy, extended therapy was associated with delayed first relapse (HR 0.80 (0.65, 0.97)) but not frequent relapses (0.92 (0.73, 1.17)), and similar annual relapse rate (MD 0.07 (-0.09, 0.23)). Extended therapy postponed the first relapse, but not frequent relapses, in patients < 2.5 years old and those of Asian or non-Western European ethnicity. Adjusted IPD meta-analyses did not find benefit of extended therapy in reducing the risks of first or frequent relapses. Multivariate one-stage meta-analyses showed that older age (≥ 2.5 years) and higher cumulative initial prednisolone dose (≥ 3.135 g/m LIMITATIONS: Few studies; heterogeneity in duration of therapy among studies and study eligibility; inability to examine the independent impact of dose and duration on outcomes. CONCLUSIONS AND IMPLICATIONS OF KEY

findingsAge at onset and cumulative initial dose of prednisolone, and not duration of extended therapy, determine disease course in pediatric steroid-sensitive nephrotic syndrome. The benefit of extending initial therapy on risk of first and frequent relapses in young patients requires examination in controlled trials using BSA-based dosing. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42021291537.