Short-Term Effects of Rituximab in Children with Steroid- and Calcineurin-Dependent Nephrotic Syndrome

Abstract

SummaryBackground 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, & measurementsThis 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 Ϯ 4 years) with INS dependent on prednisone and calcineurin inhibitors for Ͼ12 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 ϭ 0.029). Probabilities of being drug-free at 3 months were 62.9% and 3.7%, respectively (P Ͻ 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.

Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases

“…RTX has been used with some success in children with steroid-dependent idiopathic nephrotic syndrome, as shown in several case reports [81], [82], [83] and [84]. A randomized clinical trial of 54 children with steroid-and calcineurin inhibitordependent nephrotic syndrome treated with RTX versus standard therapy showed that proteinuria decreased by 70% more in the RTX arm [85]. Importantly, 63% of patients treated with RTX were drug-free at 3 months versus 3.7% in the control arm.…”

Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children

“…Between 2011 and 2015, five clinical trials on the use of rituximab in idiopathic nephrotic syndrome were reported: four as journal articles (27)(28)(29)(30) and one in abstract form. Results of four prospective studies were also published in the same period (see below) (27,31,32).…”

“…Tables 2 and 3 summarize the key characteristics and findings from these randomized controlled trials. One trial enrolled children with idiopathic nephrotic syndrome maintained in remission with high-dose steroids alone (27), three trials enrolled children maintained in remission with steroids and calcineurin inhibitors (28,29), and one trial assessed the effect of rituximab in children with nephrotic syndrome resistant to both steroids and calcineurin inhibitors (30). Figure 2 presents a flow chart of treatment of idiopathic nephrotic syndrome based on randomized controlled trials.…”

“…Two trials have studied the effects of rituximab in these more complex forms of idiopathic nephrotic syndrome. One study enrolled 54 children with at least a 1-year history of nephrotic syndrome who had been maintained in remission for at least 6 months (28). In this study, participants were stratified on the basis of the presence or absence of signs of drug toxicity versus steroids (i.e., growth retardation, cataract, and osteoporosis) and/or calcineurin inhibitors (i.e., hypertension and neurologic and renal signs) and were randomly assigned to continue the combination therapy alone or to receive one (if toxicity was absent) or two (if toxicity was present) doses of rituximab (375 mg/m 2 each).…”

Rituximab in Steroid-Resistant Nephrotic Syndrome in Children

“…A randomized controlled study by Ravani et al 19 has also shown noninferiority of rituximab therapy in children with nephrotic syndrome who were resistant to only steroid therapy but dependent on both steroids and CNIs. In this trial, 27 patients were randomized to receive one to two doses of rituximab followed by withdrawal of prednisone and CNIs over 6 weeks, whereas 27 patients continued standard therapy with prednisone and CNIs.…”