Recent Clinical Trials Insights into the Treatment of Primary Membranous Nephropathy

Immunosuppressive therapy is mandatory for primary membranous nephropathy with persistent nephrotic proteinuria or anti-phospholipase A2 receptor antibodies, reduced kidney function, or another risk factor for progression. Rituximab has demonstrated efficacy for proteinuria remission compared with renin-angiotensin system blockade or cyclosporine in two well-powered randomized controlled trials. More recently, STARMEN showed that alternating glucocorticoid-cyclophosphamide is superior to sequential tacrolimus-rituximab for proteinuria remission, although it was associated with a higher risk of non-serious adverse events. However, sequential tacrolimus-rituximab involved delayed lower dose rituximab and was the worst-performing rituximab regimen among those tested in randomized clinical trials. The RI-CYCLO pilot study did not demonstrate superiority of glucocorticoid-cyclophosphamide over rituximab and found no difference in adverse events. Overall, STARMEN and RI-CYCLO confirmed the efficacy of glucocorticoid-cyclophosphamide in patients with high-risk membranous nephropathy and the role of rituximab as a valid alternative. However, none of the trials tested an optimized rituximab protocol involving a second rituximab cycle before declaring treatment failure. Calcineurin inhibitors should be considered third-line drugs and sequential use of calcineurin inhibitor rituximab did not add over rituximab-only regimens. We critically review recent randomized controlled trials, propose a research agenda, and call for multinational pragmatic trials that enroll patients at referral centers to address unmet research needs.