Rituximab is a safe and effective long-term treatment for children with steroid and calcineurin inhibitor-dependent idiopathic nephrotic syndrome

Abstract

In children with idiopathic nephrotic syndrome, rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin inhibitors. Long-term effects including the number of repeated infusions to maintain remission are unknown. To test this, we treated 46 consecutive children with idiopathic nephrotic syndrome lasting for at least 1 year (mean 6.3 years), maintained in remission with oral prednisone and calcineurin inhibitors. They received 1-5 rituximab courses during a median follow-up of 3 years. Oral agents were tapered after each infusion, and completely withdrawn within 45 days. Rituximab was well tolerated. Six-month probabilities of remission were 48% after the first infusion and 37% after subsequent infusions. One- and 2-year-remission probabilities were, respectively, 20 and 10%. Median time intervals between complete oral-agent withdrawal and relapse were 5.6 and 8.5 months, respectively, following the first and subsequent courses. The time to reconstitution of CD20 cells correlated with the duration of remission, but was not associated with variation in FcyR, CD20, or SMPDL-3B polymorphisms. Podocyte Src phosphorylation was normal. Thus, rituximab can be safely and repeatedly used as a prednisone and calcineurin inhibitor-sparing therapy in a considerable proportion of children with dependent forms of idiopathic nephrotic syndrome. Further study is needed to identify patients who will benefit most from rituximab therapy.

Figure 1

Outcome definitions: We studied probability of prednisone and calcineurin-inhibitor-free remission (top) for at least 6 and 12 months (primary outcomes; no children were excluded from these analyses). Remission (absence of proteinuria) could be attained with complete withdrawal of both prednisone (P) and calcineurin-inhibitors (C) or either of them. We studied also time to relapse (proteinuria or need to reintroduce prednisone or calcineurin-inhibitors) after successful tapering (bottom). This analysis included only children who completed drug withdrawal, as children who failed to complete drug withdrawal could not be considered at risk for relapse (secondary outcome).

Figure 2

Distribution of 6 and 12-month remissions after the initial treatment (top), and after any treatment (bottom), according to the drugs that were successfully withdrawn: 6M and 12M remissions indicate remission for 6 and 12 months; P/C indicates prednisone and calcineurin-inhibitors-free remission; P indicates prednisone-free remission; and C indicates calcineurin-inhibitor-free remission. Absolute frequencies (%) are reported for each outcome.

Figure 3

Time to relapse in patients who completed prednisone and/or calcineurin-inhibitor tapering and withdrawal The three Kaplan-Meier survival curves (with 95% confidence intervals) estimate the time to relapse according to whether remission (absence of proteinuria) was maintained without prednisone and calcineurin-inhibitors (‘P and C’; left plot); avoiding prednisone (‘P’, with or without use of calcineurin-inhibitors; mid plot); or avoiding calcineurin-inhibitors (‘C’, with or without use of prednisone; right plot).

Figure 4

Proposed strategies to maintain remission in prednisone and calcineurin inhibitor-dependent idiopathic nephrotic syndrome. P indicates prednisone; CNI indicates calcineurin inhibitors; RTX indicates rituximab; TAC indicates tacrolimus; MMF indicates mycophenolate mofetil; bold indicate comparisons currently being tested in clinical trials (EudraCT number 2010-020184-20).