Among all glomerular diseases, membranous nephropathy is perhaps the one in which greater progress has been made during the last 5 years, both in the understanding of the pathogenesis and treatment. Myriad target antigens have been identified so far, which has led to the proposal of reclassification of membranous nephropathy based on the underlying pathogenesis (1). In addition, the latest results from clinical trials on membranous nephropathy have sparked renewed interest in the management of the disease (2).
Five landmark trials—Ramachandran et al. (3), GEMRITUX (4), MENTOR (5), and STARMEN (6), together with a fifth trial (RI-CYCLO) (7), which essentially was a pilot study (Figure 1, Table 1)—have been performed on membranous nephropathy. These results have had a significant impact on current patient management, some of them reflected in the latest Kidney Disease: Improving Global Outcomes (KDIGO) guidelines (8).
Summary of recent trials on membranous nephropathy
In the trial by Ramachandran et al. (3), the authors compared the efficacy of tacrolimus corticosteroids with cyclical corticosteroids-cyclophosphamide at 6 and 12 months, showing comparable results, although with different adverse effect profiles (mainly higher incidence of nephrotoxicity in the calcineurin inhibitor arm).
The GEMRITUX trial (4) evaluated the effects of rituximab compared with non-immunosuppressive treatment. Interestingly, no significant differences were observed within the first 6 months, which corresponded to the primary endpoint. However, in the extended follow-up beyond 6 months, the remission rate was significantly greater in patients treated with rituximab.
The MENTOR trial (5) compared rituximab with cyclosporine, and although no significant differences were observed in the rate of complete/partial remissions at 12 months (60% vs. 52%), at 24 months, a significantly greater number of patients remained in remission in the rituximab arm, mostly due to a large number of relapses after the discontinuation of cyclosporine. Thus, rituximab was found to be non-inferior to cyclosporine for induction of remission at 12 months but statistically superior at 24 months in terms of maintenance of remission.
The STARMEN trial (6) compared a sequential regimen based on tacrolimus and rituximab, with cyclical corticosteroids-cyclophosphamide. The primary outcome (complete/partial remission at 24 months) occurred in 84% in the corticosteroids-cyclophosphamide group versus 58% in the tacrolimus-rituximab group, with the rate of complete remissions being significantly greater in the former group. Remarkably, the number of relapses was also lower in the group treated with corticosteroids-cyclophosphamide.
Finally, the RI-CYCLO trial (7) aimed to assess the effect of rituximab compared with a cyclical corticosteroids-cyclophosphamide scheme for the induction of remission. At 12 months, the number of patients with complete remission was lower in the rituximab arm compared with corticosteroids-cyclophosphamide (16% vs. 32%), whereas at 24 months, complete remission was similar (42% vs. 35%). Thus, the authors concluded that there was no superiority of rituximab versus the cyclical regimen, although a pragmatic comparison of these two regimens would require a global non-inferiority trial.
Based on some of these trials, the latest KDIGO guidelines suggest different therapeutic approaches according to risk stratification (2, 8). For patients at low risk, immunosuppressive therapy may not be required unless additional risk factors for disease progression are present. For patients at moderate risk, the guideline suggests a wait-and-see approach or immunosuppressive therapy based on rituximab or calcineurin inhibitor ± glucocorticoids. Conversely, for high-risk patients, rituximab, cyclophosphamide plus glucocorticoids, or calcineurin inhibitor plus rituximab are suggested.
Taken together, these trials represent a major step forward for evidence-based membranous nephropathy and will likely contribute to a more personalized treatment. Nevertheless, further research is needed to fill several knowledge gaps in both the diagnosis and treatment of several resistant forms of the disease.
Bobart SA, et al. A target antigen-based approach to the classification of membranous nephropathy. Mayo Clin Proc 2021; 96:577–591. doi: 10.1016/j.mayocp.2020.11.028
Caravaca-Fontán F, et al. The management of membranous nephropathy—an update. Nephrol Dial Transplant 2022; 37:1033–1042. doi: 10.1093/ndt/gfab316
Ramachandran R, et al. Tacrolimus combined with corticosteroids versus modified Ponticelli regimen in treatment of idiopathic membranous nephropathy: Randomized control trial. Nephrology (Carlton) 2016; 21:139–146. doi: 10.1111/nep.12569
Dahan K, et al. Rituximab for severe membranous nephropathy: A 6-month trial with extended follow-up. J Am Soc Nephrol 2017; 28:348–358. doi: 10.1681/ASN.2016040449
Fervenza FC, et al. Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med 2019; 381:36–46. doi: 10.1056/NEJMoa1814427
Fernández-Juárez G, et al. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy. Kidney Int 2021; 99:986–998. doi: 10.1016/j.kint.2020.10.014
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, Fernández-Juárez G The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy. Kidney Int 2021; 99: 986– 998. doi: 10.1016/j.kint.2020.10.014
Scolari F, et al. Rituximab or cyclophosphamide in the treatment of membranous nephropathy: The RI-CYCLO randomized trial. J Am Soc Nephrol 2021; 32:972–982. doi: 10.1681/ASN.2020071091
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the management of glomerular diseases. Kidney Int 2021; 100:S1–S276. doi: 10.1016/j.kint.2021.05.021