Safety and efficacy of sirolimus combined with cyclosporine in primary membranous nephropathy: a randomized controlled trial
Background: Calcineurin inhibitors like cyclosporine are standard treatments for membranous nephropathy (MN), but their use is limited by nephrotoxicity. Optimizing therapy to preserve kidney function and promote immunological remission is essential. Combining sirolimus with cyclosporine may achieve clinical outcomes comparable to cyclosporine alone, while enhancing kidney function and antibody clearance.
Methods: In this single-center, randomized, phase 2 trial, 74 patients with biopsy-confirmed primary MN and persistent proteinuria (>3.5 g/day) after 6 months of supportive care were enrolled. Participants were randomized (1:1) to receive either cyclosporine monotherapy or combination therapy with cyclosporine and sirolimus for 12 months.
Results: At 12 months, composite clinical remission was Rapamycin achieved in 72% (26/36) of patients in the combination group and 67% (24/36) in the monotherapy group (95% CI for noninferiority: 0.48–3.56). At 6 months, immunological remission—defined as seroconversion of anti-PLA2R antibodies—was significantly higher with combination therapy (70% vs. 20%, P < 0.001). Kidney function was better preserved in the combination group, with a smaller decline in eGFR (-7.1 vs. -21.3 ml/min/1.73 m², P < 0.001). One serious adverse event occurred in the combination group, compared to none in the monotherapy group (P = 0.317).
Conclusions: Sirolimus combined with cyclosporine was noninferior to cyclosporine alone in inducing clinical remission in MN and provided superior outcomes in immunological remission and kidney function preservation.