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.

Detection and monitoring PLA 2 R autoantibodies by LIPS in membranous nephropathy

“…We next compared the efficacy of the PLA 2 R-NanoLuc LIPS test against ELISA for longitudinal autoantibody monitoring in the treatment cohort (Patients 1–13) (Waldman et al, 2016). In the pre-treatment samples, eleven of 13 (85%) patients had detectable circulating autoantibodies against PLA 2 R based on the LIPS assay (Fig.…”

“…Since many studies have shown that the concentrations of anti-PLA 2 R antibodies correlate with urinary protein excretion and disease activity (Beck et al, 2011; Hoxha et al, 2012; Kanigicherla et al, 2013; Radice et al, 2016; Timmermans et al, 2015; Waldman et al, 2016), the relationship between PLA 2 R autoantibody levels determined by NanoLuc LIPS and changes in proteinuria were evaluated in the treatment cohort. As shown in Fig.…”

“…A subset of the MN cohort (n=13) were treatment-naïve patients with primary MN enrolled in an experimental clinical trial. They received immunosuppression with a combination of rituximab and cyclosporine (“treatment cohort’) as described in (Waldman et al, 2016) and were followed longitudinally. Serum and urine samples were collected at baseline (before initiating therapy) and at 3 month intervals over the 24 month trial period to evaluate changes in autoantibody levels and clinical parameters (e.g.…”

“…Serum and urine samples were collected at baseline (before initiating therapy) and at 3 month intervals over the 24 month trial period to evaluate changes in autoantibody levels and clinical parameters (e.g. protein excretion based on 24 hour urine collection) (Waldman et al, 2016). Partial and clinical remission were defined as urinary protein excretion of ≤3.5 g/24 h and <0.3g/24 h, respectively.…”

“…Partial and clinical remission were defined as urinary protein excretion of ≤3.5 g/24 h and <0.3g/24 h, respectively. For the purpose of validating the LIPS assay, all baseline MN samples were tested by Western blotting (Beck et al, 2009) and/or a commercially available ELISA kit (EUROIMMUN US, Mountain Lakes, NJ) as previously described (Waldman et al, 2016) and classified as PLA 2 R seropositive or seronegative. ELISA titer values higher than 20 RU/ml were considered positive per the manufacturer’s protocol.…”