IMPORTANCE Calcineurin inhibitors are an established first-line corticosteroid-sparing therapy for patients with corticosteroid-dependent nephrotic syndrome (CDNS), whereas B-lymphocyte-depleting therapy is mostly used as a rescue for calcineurin inhibitor-resistant cases. The positive efficacy and safety profile of rituximab raises the question of whether it could be used as a first-line alternative to calcineurin inhibitor therapy. OBJECTIVE To compare the efficacy of rituximab and tacrolimus in maintaining relapse-free survival among children with CDNS. DESIGN, SETTING, AND PARTICIPANTS A parallel-arm, open-label, randomized clinical trial was performed from May 8, 2015, to September 20, 2016, with 1-year follow-up in a single-center, tertiary care unit. A total of 176 consecutive children aged 3 to 16 years with CDNS not previously treated with corticosteroid-sparing agents were screened for eligibility. INTERVENTIONS The children received either tacrolimus (along with tapering alternate-day prednisolone) for 12 months or a single course of rituximab (2 infusions of 375 mg/m 2). MAIN OUTCOMES AND MEASURES Twelve-month relapse-free survival in the intention-to-treat population. RESULTS Of the 176 children screened for eligibility, 120 were randomized and all but 3 patients completed 1 year of follow-up. The groups were comparable, with mean (SD) age of 7.2 (2.8) years, 32 boys (53.3%) in each group, mean (SD) disease duration of 2.5 (1.5) years and 2.3 (1.7) in the tacrolimus and rituximab groups, respectively, disease duration less than 1 year among 15 children (25.0%) in each group, median (interquartile range) of 4 (3-5) relapses in each group, and mean (SD) cumulative prednisolone dose of 246 (48) mg/kg and 239 (52) mg/kg in the prestudy year in the tacrolimus and rituximab groups, respectively. Rituximab therapy was associated with a higher 12-month relapse-free survival rate than tacrolimus (54 [90.0%] vs 38 [63.3%] children; P < .001; odds ratio, 5.21; 95% CI, 1.93-14.07). Among the patients who experienced relapse, median time to first relapse was 40 weeks in the rituximab group and 29 weeks in the tacrolimus group. Only 2 patients in the rituximab group had more than 1 relapse during the study period compared with 10 patients in the tacrolimus group. The cumulative corticosteroid dose during the 12-month study period was lower with rituximab compared with tacrolimus (mean [SD], 25.8 [27.8] vs 86.3 [58.0] mg/kg). Although both treatments were well tolerated, mild to moderate infections were twice as common in the tacrolimus group (26 [43.3%] vs 13 [21.7%] events). CONCLUSIONS AND RELEVANCE In children with CDNS, rituximab appears to be more effective than tacrolimus in maintaining disease remission and minimizing corticosteroid exposure and, given its good tolerability and lack of nephrotoxic effects, may be considered as first-line corticosteroid-sparing therapy.

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Long term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD 5. Yet, 82% of adult patients have CKD 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients.

Background: Long-term outcomes following multiple rituximab courses among children with frequently-relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown. Methods: A retrospective cohort study at 16 pediatric nephrology centers from 10 countries in Asia, Europe, and North America included children with FRSDNS who received ≥2 rituximab courses. Primary outcomes were relapse-free survival and adverse events. Results: 346 children (age 9.8 years, IQR 6.6-13.5; 73% boys) received 1149 rituximab courses. 145, 83, 50, 28, 22, and 18 children received 2, 3, 4, 5, 6 and ≥7 courses, respectively. Median follow-up was 5.9 years (IQR, 4.3-7.7). Relapse-free survival differed by treatment courses (clustered log-rank test p<0.001). Compared to the first course (10.0 months, 95% CI, 9.0-10.7), relapse-free period and relapse risk progressively improved following subsequent courses (12.0-16.0 months; HRadj, 0.03-0.13; 95% CI, 0.01-0.18; ps<0.001). B-cell depletion duration remained similar with repeated treatments (6.1 months, 95% CI, 6.0-6.3). Adverse events were mostly mild, most commonly hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 vs 3.3 years; p=0.05) and at first rituximab (8.0 y vs 10.0 years; p=0.01) and history of steroid resistance (28% vs 18%; p=0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% vs 20%, p=0.04). Upon last follow-up, 332 children (96%) had normal kidney function. Conclusion: Children receiving repeated rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable but significant complications can occur. These findings support repeated rituximab use in FRSDNS.