Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial

Abstract

Background and objectives: Prednisone and calcineurin inhibitors are the mainstay therapy of idiopathic nephrotic syndrome (INS) in children. However, drug dependence and toxicity associated with protracted use are common. Case series suggest that the anti-CD20 monoclonal antibody rituximab (RTX) may maintain disease remission.

Design, setting, participants, & measurements: This open-label randomized controlled trial was powered to show that a strategy based on RTX and lower doses of prednisone and calcineurin inhibitors was noninferior to standard doses of these agents in maintaining 3-month proteinuria as low as baseline or up to 1 g/d greater (noninferiority margin). Participants were stratified by the presence of toxicity to prednisone/calcineurin inhibitors and centrally assigned to add RTX (Mabthera, 375 mg/m(2) intravenously) to lower doses of standard agents or to continue with current therapy alone. The risk of relapse was a secondary outcome.

Results: Fifty-four children (mean age 11 ± 4 years) with INS dependent on prednisone and calcineurin inhibitors for >12 months were randomized. Three-month proteinuria was 70% lower in the RTX arm (95% confidence interval 35% to 86%) as compared with standard therapy arm (intention-to-treat); relapse rates were 18.5% (intervention) and 48.1% (standard arm) (P = 0.029). Probabilities of being drug-free at 3 months were 62.9% and 3.7%, respectively (P < 0.001); 50% of RTX cases were in stable remission without drugs after 9 months.

Conclusions: Rituximab and lower doses of prednisone and calcineurin inhibitors are noninferior to standard therapy in maintaining short-term remission in children with INS dependent on both drugs and allow their temporary withdrawal.

Figure 1.

Number of patients who were screened for the study, who underwent randomization, and who completed the study.

Figure 2.

The plots summarize the distribution of proteinuria (g/d [log-scale]), prednisone [PDN] in mg/kg per day, and proportion of children on full dose of calcineurin inhibitors [CNI, i.e., cyclosporine or tacrolimus] over time in weeks from randomization (time zero). Dark gray bars refer to patients assigned to RTX-based strategy; light gray bars refer to standard therapy strategy. The plot on the left (all patients) refers to model 1 in Table 3; the middle and right plots refer to model 2 in Table 3. The line across the box plots (proteinuria and prednisone plots) is the median, the box hinges are the 25th and 75th percentiles, and the outliers are represented as dots lying beyond 1.5 times the interquartile range.

Figure 3.

Twelve-month relapse-free survival from randomization in children assigned to RTX therapy (n = 27). Tapering of steroids and calcineurin inhibitors started 30 days after RTX infusion and was completed in 45 days.