A Target Antigen–Based Approach to the Classification of Membranous Nephropathy

Objective: To describe the clinical and pathological phenotype of membranous nephropathy (MN) associated with M-type-phospholipase–A₂-receptor (PLA₂R), thrombospondin-type-1-domain-containing-7A (THSD7A), semaphorin 3B (SEMA3B), neural-epidermal-growth-factor-like-1-protein (NELL-1), protocadherin 7 (PCDH7), exostosin 1/exostosin 2 (EXT1/EXT2) and neural cell adhesion molecule 1 (NCAM-1) as target antigens. Methods: A retrospective cohort of 270 adult patients with biopsy-proven MN diagnosed between January 2015 and April 2020 was classified as PLA₂R-, THSD7A-, SEMA3B-, NELL-1–, PCDH7-, EXT1/EXT2-, NCAM-1–associated or septuple-negative MN using serologic tests, immunostaining, and/or mass spectrometry. Clinical, biochemical, pathologic, and follow-up data were systematically abstracted from the medical records, including disease activity of conditions traditionally associated with MN and occurring within 5 years of MN diagnosis. Results: Patients with PLA₂R-associated MN were predominantly middle-aged white men without associated disease. The presence of associated disease did not affect the clinical and pathologic characteristics of PLA₂R-associated MN, suggesting that they were coincidental rather than causally linked. THSD7A-, NELL-1–, PCDH7-, and NCAM-1–associated MN were rare and SEMA3B-associated MN was not discovered in our cohort. EXT1/EXT2-associated MN was primarily diagnosed in younger women with active systemic autoimmunity. A significant proportion of septuple-negative patients had associated malignancy or systemic autoimmunity. Conclusion: The widely used distinction between primary and secondary MN has limitations. We propose a refined terminology that combines the target antigen and associated disease to better classify MN and guide clinical decision making.