Membranous nephropathy: Pilot study of a novel regimen combining cyclosporine and Rituximab

Abstract

Introduction: There is broad consensus that high grade basal proteinuria and failure to achieve remission of proteinuria are key determinants of adverse renal prognosis in patients with primary membranous nephropathy. Based on the fact that current regimens are not ideal due to short and long-term toxicity and propensity to relapse after treatment withdrawal, we developed a treatment protocol based on a novel combination of rituximab and cyclosporine which targets both the B and T cell limbs of the immune system. Herein, we report pilot study data on proteinuria, changes in autoantibody levels and renal function that offer a potentially effective new approach to treatment of severe membranous nephropathy.

Methods: Thirteen high-risk patients defined by sustained high-grade proteinuria (mean 10.8 g/d) received combination induction therapy with rituximab plus cyclosporine for 6 months, followed by a second cycle of rituximab and tapering of cyclosporine during an 18 month maintenance phase.

Results: Mean proteinuria decreased by 65% at 3 months and by 80% at 6 months. Combined complete or partial remission was achieved in 92% of patients by 9 months; 54% achieved complete remission at 12 months. Two patients relapsed during the trial. All patients with autoantibodies to PLA2R achieved antibody depletion. Renal function stabilized. The regimen was well tolerated.

Discussion: We report these encouraging preliminary results for their potential value to other investigators needing prospectively collected data to inform the design and power calculations of future randomized clinical trials. Such trials will be needed to formally compare this novel regimen to current therapies for membranous nephropathy.

Keywords: Membranous nephropathy; cyclosporine; nephrotic syndrome; rituximab.

Figures

Figure 1

Box plots of urinary protein excretion from time of diagnosis (biopsy) to study initiation/enrollment (time 0) to 24 months. Proteinuria increased during the observation phase (from diagnostic biopsy to time 0). After initiation of therapy, there was a rapid reduction in proteinuria within 3 months. The top and bottom of the box are the estimated 75th and 25th percentiles, respectively. The horizontal lines and “+” signs within each box represent the median and mean values, respectively. The vertical dashes denote the largest as well as the smallest data point that is within 1.5 times the interquartile range (75th to 25th percentile) above the 75th percentile or below the 25th; data points outside of this range are denoted by open circles. After relapse, patients were treated off protocol. Outcomes and efficacy data of relapsed patients from that point forward were not included in the analysis.

Figure 2

Box plots showing changes in eGFR (CKD-EPI) from the time of diagnosis (biopsy) to study initiation/enrollment (time 0) to 24 months. Estimates of changes in eGFR over various intervals are based on mixed-effects models. During the observation phase (defined as time from biopsy to start of study drugs at time 0), there was a decline in renal function; the slope of decline in eGFR was –1.89 ml/min per 1.73 m2 per month. Initiation of induction therapy was associated with further decline in renal function that improved as cyclosporine was tapered and discontinued during the maintenance phase (starting at month 7). The change in eGFR during the induction phase was –4.07 ml/min per 1.73 m2 and +11.92 ml/min per 1.73 m2 during the maintenance phase (7–24 months). By 24 months, there was improvement in renal function compared to enrollment (time 0) values. The top and bottom of the box are the estimated 75th and 25th percentiles. The horizontal lines and “+” signs within each box represent the median and mean values, respectively. The vertical dashes denote the largest as well as the smallest data point that is within 1.5 times the interquartile range (75th to 25th percentile) above the 75th percentile or below the 25th; data points outside of this range are denoted by open circles. P values compare 0 versus 6 months, 6 months versus 24 months, and 0 versus 24 months.