Rituximab in Membranous Nephropathy: Not All Studies Are Created Equal

Many prospective studies and a recent randomized controlled trial have shown that the B-cell-depleting monoclonal antibody, rituximab, safely promotes the remission of nephrotic syndrome in approximately 65% of patients with membranous nephropathy (MN). Mechanistic studies have indicated that rituximab-induced proteinuria reduction is associated with clearance of anti-podocyte antigens phospholipase 2 receptor autoantibodies and subepithelial immune complexes, the hallmarks of the disease. A recently published study reported results which, at first sight, looked less favorable and implied that, due to a publication bias against negative results, the efficacy of rituximab in MN might be overestimated. Since patients received only one or 2 rituximab administrations, the authors suggest that when rituximab is used, higher doses and longer treatments should be considered. In this study, we highlight limitations of the study and warn against an oversimplified interpretation of the data. Though information on the optimal dose of rituximab to use in MN is still limited, available data from studies with predefined rituximab administration protocols collectively support the concept of titrating rituximab to the number of circulating B-cells that are invariably depleted after the first or second administration. Additional doses may increase the risk of adverse effects and related costs without augmenting efficacy. Importantly, underpowered studies with inconclusive results should not be confused with negative studies formally proving a neutral effect of a treatment. Until data from ad hoc designed clinical trials are available, the B-cell-driven protocol should be the preferred regimen, since it is similarly effective, but safer and more cost effective than other protocols employing multiple rituximab administrations.