Safety and efficacy of sirolimus combined with cyclosporine in primary membranous nephropathy: a randomized controlled trial.

Background: Calcineurin inhibitors, such as cyclosporine, are primary treatments for membranous nephropathy (MN). Optimizing this regimen is crucial to reduce nephrotoxicity and enhance immunological remission. Sirolimus, when combined with cyclosporine, may offer non-inferior clinical remission to cyclosporine monotherapy, while improving kidney function preservation and antibody clearance.

Methods: This single-center, randomized controlled, phase 2 clinical trial involved 74 patients with biopsy-proven primary MN and persistent proteinuria > 3.5 g/d, despite 6 months of supportive care. Participants were randomly assigned (1:1) to receive either sirolimus plus cyclosporine or cyclosporine monotherapy for 12 months.

Results: At 12 months, composite remission was achieved in 26 of 36 patients (72%) receiving combination therapy and in 24 of 36 (67%) receiving cyclosporine alone (95% confidence interval for noninferiority: 0.48-3.56). Immunological remission, defined as anti-phospholipase A2 receptor antibody conversion from positive to negative, was significantly higher in the combination group (70% vs. 20%, P < 0.001) at 6 months. Moreover, eGFR decline was significantly attenuated in the combination group (ΔeGFR: -7.1 vs. -21.3 ml/min/1.73m, P < 0.001) at 12 months. 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 monotherapy in achieving clinical remission in MN and demonstrated superior benefits in immunological remission and kidney function preservation.