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

Mayo Clin Proc. 2021 Mar;96(3):577-591. doi: 10.1016/j.mayocp.2020.11.028.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antigens / metabolism*
  • Autoantibodies / metabolism*
  • Cadherins / metabolism
  • Female
  • Glomerulonephritis, Membranous / immunology*
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • N-Acetylglucosaminyltransferases / metabolism
  • Neural Cell Adhesion Molecules / metabolism
  • Protocadherins
  • Receptors, Phospholipase A2 / metabolism
  • Severity of Illness Index
  • Thrombospondins / metabolism

Substances

  • Antigens
  • Autoantibodies
  • Cadherins
  • Neural Cell Adhesion Molecules
  • PCDH7 protein, human
  • PLA2R1 protein, human
  • Protocadherins
  • Receptors, Phospholipase A2
  • THSD7A protein, human
  • Thrombospondins
  • N-Acetylglucosaminyltransferases
  • exostosin-1
  • exostosin-2