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.

BACKGROUND: Rituximab is being increasingly used in children with idiopathic nephrotic syndrome resistant to standard treatments. In spite of good initial response, rituximab responders always remain prone to further relapse, necessitating either repeat course of rituximab or addition of another steroidsparing immunosuppressant.METHODS: A retrospective analysis of baseline clinico-pathologic presentation and treatment outcome (complete remission, partial remission, or no response) was performed among 24 children with refractory-idiopathic SRNS over a follow-up period of 24 months. Children received 2 to 4 rituximab infusions (375 mg/m 2 weekly) depending on circulating B-cell level. At 3-month follow-up, a second course of rituximab was administered (if .5 B cells/mm 3 ) along with MMF (1200 mg/m 2 per day) maintenance therapy.RESULTS: Of 24 patients, 54% (13/24) and 46% (11/24) had minimal change disease and focal segmental glomerulosclerosis, respectively, on renal histopathology. After the first course of rituximab, 21% (5/24) of children achieved complete remission; however, most (4/5) of them relapsed again at a median interval of 53 (interquartile range 46-72) days. Depending on response to the first course of rituximab, MMF was started on 15 children at 3 months. After 6 months, 67% (10/15) of children on MMF achieved complete remission and 33% (5/15) remained at partial remission. At 24 months overall, 25% (6/24) and 42% (10/24) of children were in complete remission and partial remission, respectively; 33% (5/15) of children continued sustained complete remission after postrituximab-MMF maintenance therapy in comparison with no sustained complete remission with rituximab alone at 24 months (P , .001).CONCLUSIONS: MMF may be an effective and safe maintenance therapy to consider as an additive immunosuppressant after induction with rituximab in maintaining remission among children with refractory SRNS.

Although there are serious safety concerns regarding tacrolimus, it is more effective than MMF or levamisole in maintaining relapse-free survival. However, unlike MMF, the relative efficacy of tacrolimus in preventing further relapses is seen only when the patient is on the drug. Taking together the long-term efficacy and safety data observed, MMF appears as a safe and effective alternative to tacrolimus in managing pediatric FRNS/SDNS.

Efficacy and medium-term safety of rituximab- and MMF-based protocol in managing children with MPA was evident in this study.