Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy

Paul is a 51-year-old man who was recently diagnosed with nephrotic syndrome due to primary membranous nephropathy. Despite good blood pressure management and a low-protein, low-salt diet, Paul’s recent work up shows persistent proteinuria of 6 g/day and worsening creatinine levels (from 1.1 to 1.5 mL/min/1.73m²).  What are the options for the next step in his care?

Current management strategies in patients with persistent nephrotic syndrome have relied on immunosuppressive therapy with a regimen of alternating glucocorticoids and cyclophosphamide or a calcineurin inhibitor (e.g., cyclosporine). The anti-CD20 monoclonal antibody rituximab has shown promise in the treatment of membranous nephropathy owing to the selective depletion of B-cell dysfunction that appears to be central to the pathogenesis of this condition.

In the open-label, randomized, noninferiority Membranous Nephropathy Trial of Rituximab (MENTOR) published in the NEJM, rituximab was found to be superior to cyclosporine — the current preferred therapy — in inducing and maintaining remission of proteinuria. At 24 months, 60% of patients treated with rituximab had partial or complete remission of proteinuria versus only 20% of patients treated with cyclosporine. The importance of these findings is that rituximab has been associated with better preservation of kidney function and a lower incidence of relapse, compared with cyclosporine.

The following NEJM Journal Watch summary explains the study and results in further detail:

Allan S. Brett, MD reviewing Fervenza FC et al. N Engl J Med 2019 Jul 4 Ruggenenti P and Remuzzi G. N Engl J Med2019 Jul 4

Membranous nephropathy is a common cause of nephrotic syndrome in adults. Many patients can be observed without initiating immunosuppressive treatment; however, patients at substantial risk for progressive disease (according to serial measurements of urine protein and glomerular filtration rate) typically are treated with cyclophosphamide plus glucocorticoid or with a calcineurin inhibitor (e.g., cyclosporine). In this industry-funded randomized trial, 130 adults with membranous nephropathy who were at moderate-to-high risk for progression received either cyclosporine or the anti-CD20 monoclonal antibody rituximab. At enrollment, median urinary protein was 8.9 g per 24 hours, median serum creatinine was 1.3 mg/dL, and median serum albumin was 2.5 g/dL.

At 24 months, the incidence of complete remission (≤0.3 g proteinuria/24 hours) or partial remission (≥50% reduction in proteinuria, to a level between 0.3 and 3.5 g/24 hours) was significantly higher with rituximab than with cyclosporine (60% vs. 20%). The incidence of serious adverse events was somewhat higher with cyclosporine than with rituximab (31% and 17%; P=0.06).

Comment: Currently, rituximab generally is reserved for patients with membranous nephropathy whose disease has been resistant to standard therapies. These results suggest that rituximab might become a first-line treatment option in selected patients.

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Krista is a 2019-2020 editorial fellow at the New England Journal of Medicine. She is from Nassau, Bahamas where she is training in general surgery at the University of the West Indies.