Exostosin 1/exostosin 2–associated membranous nephropathy

Sanjeev Sethi, Benjamin J. Madden, Hanna Debiec, M. Cristine Charlesworth, Louann Gross, Aishwarya Ravindran, Amber M. Hummel, Ulrich Specks, Fernando C. Fervenza, Pierre Ronco

Research output: Contribution to journalArticle

11 Scopus citations


Background In membranous nephropathy (MN), which is characterized by deposition of immune complexes along the glomerular basement membrane (GBM), phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain–containing 7A are target antigens in approximately 70% and 1%–5% of cases of primary MN, respectively. In other cases of primary MN and in secondary MN, the target antigens are unknown. Methods We studied 224 cases of biopsy-proven PLA2R-negative MN and 102 controls (including 47 cases of PLA2R-associated MN) in pilot and discovery cohorts. We also evaluated 48 cases of PLA2R-negative presumed primary MN and lupus MN in a validation cohort. We used laser microdissection and mass spectrometry to identify new antigens, which were localized by immunohistochemistry. Results Mass spectrometry detected exostosin 1 (EXT1) and exostosin 2 (EXT2) in 21 cases of PLA2R-negative MN, but not in PLA2R-associated MN and control cases. Immunohistochemistry staining revealed bright granular GBM staining for EXT1 and EXT2. Clinical and biopsy findings showed features of autoimmune disease, including lupus, in 80.7% of the 26 EXT1/EXT2-associated MN cases we identified. In the validation cohort, we confirmed that EXT1/EXT2 staining was detected in pure class 5 lupus nephritis (eight of 18 patients) and in presumed primary MN associated with signs of autoimmunity (three of 16 pa-tients); only one of the 14 cases of mixed class 5 and 3/4 lupus nephritis was positive for EXT1/EXT2. Tests in seven patients with EXT1/EXT2-associated MN found no circulating anti-exostosin antibodies. Conclusions A subset of MN is associated with accumulation of EXT1 and EXT2 in the GBM. Autoimmune disease is common in this group of patients.

Original languageEnglish (US)
Pages (from-to)1123-1136
Number of pages14
JournalJournal of the American Society of Nephrology
Issue number6
StatePublished - Jun 2019


ASJC Scopus subject areas

  • Nephrology

Cite this

Sethi, S., Madden, B. J., Debiec, H., Cristine Charlesworth, M., Gross, L., Ravindran, A., Hummel, A. M., Specks, U., Fervenza, F. C., & Ronco, P. (2019). Exostosin 1/exostosin 2–associated membranous nephropathy. Journal of the American Society of Nephrology, 30(6), 1123-1136. https://doi.org/10.1681/ASN.2018080852