Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children

Abstract

Rituximab, a chimeric anti-CD20 monoclonal antibody originally licensed for lymphoma, is emerging as a novel steroid-sparing agent for idiopathic nephrotic syndrome in children. The potential use of anti-CD20 monoclonal antibodies in idiopathic nephrotic syndrome has contributed to shifting the view of podocytopathies from T cell-mediated to more complex immunomediated disorders that can benefit from targeting B cells and other mediators of the early immune response. Clinical data on the use of rituximab also have implications on disease management and classification. In this review, we present results of clinical studies that support rituximab as an effective steroid-sparing agent in steroid-dependent idiopathic nephrotic syndrome. Recent randomized controlled trials suggest that potential benefits of rituximab therapy in steroid-dependent forms of idiopathic nephrotic syndrome vary depending on whether children are dependent on steroids alone or on both steroids and calcineurin inhibitors, with greater probabilities to achieve drug-free remission in the former group. Multiple-drug dependence may identify a different disease state with different prognosis and treatment options. Insufficient data are available on optimal use of rituximab as a maintenance steroid-sparing agent in these steroid-sensitive forms of the disease, including how often and for how long rituximab infusions should be repeated to maximize expected benefits and minimize potential harms. Finally, one randomized controlled trial in children with steroid-resistant idiopathic nephrotic syndrome yielded negative results. New anti-CD20 antibodies are under study in this patient population.

Keywords: T-lymphocytes; anti-CD20 monoclonal antibodies; antibodies; child; glomerular disease; humans; immunosuppressive agents; monoclonal; nephrotic syndrome; proteinuria; rituximab.

Figure 1.

Proposed mechanisms of action of rituximab in patients with nephrotic syndrome effects on all cells expressing CD20 or sphingomielin phosphodiesterase acid-like 3 b (SMPDL-3b) protein. Cells presenting CD20 or SMPDL-3b/acid sphingomyelinase (ASM) as a target and mediator of rituximab effect are included. In addition to B cells (CD20), the schematic includes podocytes that express the SMPDL-3b/ASM complex and Th17-expressing ASM. The classic view of rituximab activity implies that B cells presenting the CD20-rituximab complex undergo apoptosis, become a target of antibodies, or activate complement; their lysis is the final result of all mechanisms. Deficit in B cells produces immunologic rebounds linked to the lack of their activity. In particular, B cells may act at several levels of the immune response: They modulate adaptive immunity and regulate the T-cell compartment via CD80 and CTLA4; CD80 is a costimulatory molecule expressed by antigen-presenting cells and by B cells (6). Via SMPDL-3b/ASM, rituximab also modulates IL-17 production by Th17; CD39 and CD161 may serve as surface markers of IL-17 and modulate, in turn, ASM SMPDL-3b-mediated signal transduction (STAT3) (44). Finally, by interacting with SMPDL-3b/ASM in podocytes, rituximab may stabilize actin remodeling, which is a mechanism for proteinuria (42).

Figure 2.

A proposed flow chart for treatment of idiopathic nephrotic syndrome based on recent results from randomized controlled trials on the effectiveness of rituximab (RTX). ACEi, angiotensin-converting enzyme inhibitor; MMF, mycophenolate mofetil; OFA, ofatumumab; PDN, prednisone.