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

• Published in: Mayo Clinic proceedings Vol. 96; no. 3; pp. 577 - 591
• Main Authors: Bobart, Shane A., Tehranian, Shahrzad, Sethi, Sanjeev, Alexander, Mariam P., Nasr, Samih H., Moura Marta, Casal, Vrana, Julie A., Said, Samar, Giesen, Callen D., Lieske, John C., Fervenza, Fernando C., De Vriese, An S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-03-2021; Elsevier, Inc
• Subjects: Adult; Aged; Analysis; Antigens; Antigens - metabolism; Autoantibodies - metabolism; Cadherins - metabolism; Development and progression; Diagnosis; Ethylenediaminetetraacetic acid; Female; Glomerulonephritis; Glomerulonephritis, Membranous - immunology; Health aspects; Humans; Immunohistochemistry; Kidney diseases; Male; Mass spectrometry; Medical records; Methenamine; Middle Aged; N-Acetylglucosaminyltransferases - metabolism; Neural Cell Adhesion Molecules - metabolism; Physiological aspects; Receptors, Phospholipase A2 - metabolism; Severity of Illness Index; Thrombospondins - metabolism; United States; Canada; Minnesota; EXT; Ab; LM; IFA; IHC; NSAID; SEMA3B; MPO; SLE; NELL-1; GBM; ANCA; THSD7A; IF; MN; AD; PCDH7; ESKD; EM; aeGFR; IQR; NCAM-1; PLA2R; ANA; dsDNA; ELISA
• ISSN: 0025-6196; 1942-5546
• DOI: 10.1016/j.mayocp.2020.11.028

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.
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.
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.
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.