Successful Treatment of Membranous Glomerulonephritis with Rituximab in Calcineurin Inhibitor-Dependent Patients

Background and objectives: Calcineurin inhibitors (CNIs) induce remission of proteinuria in most nephrotic patients with membranous glomerulonephropathy (MGN). However, 60% of patients become treatment dependent and are at risk of chronic nephrotoxicity. The aim of this study was to evaluate the efficacy of rituximab in patients with long-term dependence on CNIs.Design, setting, participants, and measurements: Thirteen patients with MGN, normal renal function, and proven dependence on CNIs, despite previous treatment with other immunosuppressant drugs, received a single trial of four weekly doses of rituximab (375 mg/m²). Outcome measures were the percentage of patients with CNI withdrawal and no evidence of relapse and the percentage of patients with complete or partial remission 30 mo after CNI withdrawal.Results: After rituximab, proteinuria decreased significantly (2.5 ± 0,76 basal versus 0.85 ± 0.17 at 6 mo; P = .0003). CNIs and other immunosuppressant drugs could be withdrawn in all patients with no evidence of relapse. After CNI withdrawal, GFR increased significantly (90.3 ± 15 basal to 106.4 ± 20 at 3 mo with a mean increase of 15.3% [range 0–20]). Three patients suffered a relapse of nephrotic proteinuria 19, 23, and 28 mo after rituximab treatment; all were successfully treated with a second course of rituximab. At 30 mo, all patients were in remission.Conclusions: In patients with MGN with long-term CNI dependence, rituximab can be an effective tool to overcome dependence on CNI, thus avoiding the risk of nephrotoxicity related to the chronic exposure to these drugs.Membranous glomerulonephropathy (MGN) is the most frequent cause of nephrotic syndrome in adults. There is general agreement that patients with persistent nephrotic syndrome are at risk of developing progressive renal insufficiency (1–4). In these patients, prospective randomized clinical trials have demonstrated that the calcineurin inhibitors (CNIs) cyclosporine (5,6) and tacrolimus (7) induce complete or partial remission of proteinuria in more than 70% of patients. However, more than 60% of patients treated with CNI suffer subsequent relapses or become treatment dependent (5–8) and need prolonged therapy to maintain remission, which exposes them to the nephrotoxic effects of this drugs. Consequently, for these patients, there is a need for the development of new treatment strategies aimed at reducing the risk of chronic nephrotoxicity. MGN is an antibody-mediated disease induced by deposits of immunoglobulins and complement components on the subepithelial layer of the glomerular capillary wall (9). This immune deposition promotes injury to the glomerular filtering barrier, proteinuria, and eventual renal failure (10). Infiltration of CD-20+ cells has also been demonstrated in renal biopsies of patients with MGN (11). Results in experimental MGN have shown that the inhibition of B cell function is associated with beneficial effects on proteinuria, (12) and human studies clearly demonstrated that the inhibition of B cells with alkylating agents induces remission of the nephrotic syndrome (13). The availability of monoclonal antibodies targeted to the cell surface antigen CD-20 of B cells permits an analysis of the effect of more selective and specific B cell inhibition in the outcome of several antibody-mediated diseases in clinical studies (14). In recent years, observational studies have shown that the administration of the anti-CD20 monoclonal antibody rituximab can reduce urinary protein excretion and preserve renal function in patients with MGN and persistent nephrotic syndrome (15–19).This pilot observational study was conducted in patients with MGN with normal renal function, who experienced long-term dependence on CNI despite previous treatment with high-dose immunoglobulins and mycophenolate mofetil. The study aim was to evaluate whether a single course of rituximab could allow either dose reduction or withdrawal of CNI.