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

Abstract

Objective: To describe the clinical and pathological phenotype of membranous nephropathy (MN) associated with M-type-phospholipaseeA 2 -receptor (PLA 2 R), 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 PLA 2 R-, THSD7A-, SEMA3B-, NELL-1e, PCDH7-, EXT1/EXT2-, NCAM-1eassociated 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 PLA 2 R-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 PLA 2 R-associated MN, suggesting that they were coincidental rather than causally linked. THSD7A-, NELL-1e, PCDH7-, and NCAM-1eassociated MN were rare and SEMA3Bassociated 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.

Clinical Phenotypes and Predictors of Remission in Primary Membranous Nephropathy

“…This might explain the overall favorable clinical outcome of PLA2R-negative pMN, the clinical scenario of these patients resembling to the exostosin positivity seen in the previous study [34]. Accordingly, the shift in MN is toward a target antigen-based classification, and this approach awaits validation [35].…”

Case Report: THSD7A-Positive Membranous Nephropathy Caused by Tislelizumab in a Lung Cancer Patient

“…Herein, we describe an interesting MN case with non-small cell lung cancer after tislelizumab (a PD-1 inhibitor) (4) treatment. In particular, this patient tested positive for THSD7A antibodies, which was rare and had been proven to play an important role in the development of MN (5,6). In this case report, we described the changes in autoimmune antibodies in during the development and remission of nephropathy and highlight the possibility of humoral immunity activation as a pathogenic mechanism in ICI-related MN.…”

“…MN is an antibody-mediated autoimmune glomerular disease ( 9) that typically present with marked elevation in urine protein levels and decline in serum albumin levels and is rarely reported to be associated with ICIs therapy (10). In patients with underlying cancers, MN was also considered to be a paraneoplastic sign, especially if THSD7A antibodies were present (6,11). To our knowledge, this is the first report of THSD7A-positive MN related with ICIs therapy.…”

Coincidence or connection? A patient with concurrent Lane Hamilton Syndrome and idiopathic membranous nephropathy

“…Notably, PLA2R positive staining does not definitively diagnose a primary MN based on a recent retrospective review that suggests in limited cases there may be a secondary cause such as malignancy (5%), a systemic autoimmune disease (5%), paraproteinemia (4%), viral or bacterial infections (0.4%), and non-steroidal anti-inflammatory use (1.8%) [ 16 ]. Our suspicion for a secondary PLA2R positive MN in our patient is low, given that he had none of the above.…”