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J Am Soc Nephrol. 2019 Jun;30(6):1123-1136. doi: 10.1681/ASN.2018080852. Epub 2019 May 6.

Exostosin 1/Exostosin 2-Associated Membranous Nephropathy.

Author information

1
Department of Laboratory Medicine and Pathology, sethi.sanjeev@mayo.edu.
2
Medical Genome Facility, Proteomics Core, and.
3
Sorbonne Université, Université Pierre et Marie Curie Paris 06, and Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1155, Paris, France; and.
4
Department of Laboratory Medicine and Pathology.
5
Divisions of Pulmonary and Critical Care Medicine and.
6
Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
7
Department of Nephrology and Dialysis, Assistance Publique-Hôpitaux de Paris, Tenon Hospital, Paris, France.

Abstract

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 patients); 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.

KEYWORDS:

Immunology and pathology; membranous nephropathy; nephrotic syndrome

PMID:
31061139
PMCID:
PMC6551791
[Available on 2020-06-01]
DOI:
10.1681/ASN.2018080852

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