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Clinical Trial
. 2025 May 30;23(1):323.
doi: 10.1186/s12916-025-04173-0.

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

Fang Wang  1   2   3   4   5 , Chao Yang  1   2   3   4   5 , Yue Shu  1   2   3   4   5 , Cai-Xia Lin  1   2   3   4   5 , Yao Yao  1   2   3   4   5 , Yue Li  1   2   3   4   5 , Yi-Miao Zhang  1   2   3   4   5 , Xin Wang  1   2   3   4   5 , Li-Qiang Meng  1   2   3   4   5 , Xu-Yang Cheng  1   2   3   4   5 , Gang Liu  1   2   3   4   5 , Ming-Hui Zhao  1   2   3   4   5 , Zhao Cui  6   7   8   9   10
Affiliations
Clinical Trial

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

Fang Wang et al. BMC Med. .

Abstract

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/1.73m2, 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.

Keywords: Anti-PLA2R Antibody; Clinical Trial; Cyclosporine; Membranous Nephropathy; Sirolimus.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The trial protocol was designed by the principal investigators and approved by an independent ethics committee (approval number: 2017[1346]). The study was conducted in accordance with the Declaration of Helsinki, and all participants provided written informed consent prior to enrollment. The trial was registered with the Chinese Clinical Trial Registry (ChiCTR-INR-17012212). Consent for publication: Not applicable. This manuscript does not contain any individual person’s data in any form (including images, videos, or case details) that would require consent for publication. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of the trial. Patients were randomly assigned, in a 1:1 ratio, to receive cyclosporin + sirolimus regimen or cyclosporin monotherapy regimen
Fig. 2
Fig. 2
The urinary protein (A) and serum albumin (B) during the treatments of MN patients, with comparisons between the cyclosporin + sirolimus group and the cyclosporin monotherapy group
Fig. 3
Fig. 3
Immunology remission rates of MN patients at 3, 6, and 12 months, with comparisons between the cyclosporin + sirolimus group and the cyclosporine monotherapy group. * P < 0.05, *** P < 0.001
Fig. 4
Fig. 4
The eGFR (A) and the decline of eGFR (Δ eGFR, B) during the treatments of MN patients, with comparisons between the cyclosporin + sirolimus group and the cyclosporin monotherapy group. * P < 0.05, *** P < 0.001
Fig. 5
Fig. 5
The blood trough concentration of cyclosporin during the treatments of MN patients, with comparisons between the cyclosporin + sirolimus group and the cyclosporin monotherapy group. * P < 0.05
Fig. 6
Fig. 6
The triglyceride (A), total cholesterol (B) and low-density lipoprotein cholesterol (C) during the treatments of MN patients, with comparisons between the cyclosporin + sirolimus group and the cyclosporine monotherapy group
See this image and copyright information in PMC

References

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