Membranous Nephropathy: Advances in Diagnosis and Treatment, with an Eye on PLA2R1-Negative Forms

Membranous nephropathy (MN) is an immune complex-mediated glomerular disease defined by sub-epithelial deposits that trigger complement activation and podocyte injury. Its pathogenesis reflects loss of immune tolerance and may present as a kidney-limited autoimmune process or in association with underlying conditions (e.g., malignancy, infection, drugs, or systemic autoimmunity). Current diagnostic work-up integrates circulating antibodies—most commonly anti–phospholipase A2 receptor 1 (PLA2R1)—and kidney biopsy, which remains essential in PLA2R1-negative or atypical presentations and for antigen confirmation when serology is negative. In PLA2R1-negative MN, an expanding list of antigens is being recognized, potentially refining phenotyping and risk assessment; however, dedicated studies remain limited, and the clinical weight of many newly described antigens likely requires further validation before supporting an antigen-based classification. Uneven access to advanced diagnostics particularly affects PLA2R1-negative cases, underscoring the need for centralized testing and the development of reliable non-invasive biomarkers. Treatment has advanced with rituximab and other targeted therapies, but resistant and relapsing cases remain challenging, and the evidence base for PLA2R1-negative forms is comparatively limited. This review summarizes recent diagnostic and therapeutic advances, focusing on PLA2R1-negative MN.