Exostosin 1/Exostosin 2-Associated Membranous Nephropathy

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1123-1136
Number of pages14
JournalJournal of the American Society of Nephrology : JASN
Volume30
Issue number6
DOIs
StatePublished - Jun 1 2019

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Membranous Glomerulonephritis
Phospholipase A2 Receptors
Glomerular Basement Membrane
Lupus Nephritis
Staining and Labeling
exostosin-2
exostosin-1
Antigens
Autoimmune Diseases
Mass Spectrometry
Immunohistochemistry
Thrombospondin 1
Biopsy
Microdissection
Antigen-Antibody Complex
Autoimmunity

Keywords

  • Immunology and pathology
  • membranous nephropathy
  • nephrotic syndrome

ASJC Scopus subject areas

  • Nephrology

Cite this

Sethi, S. M., Madden, B. J., Debiec, H., Charlesworth, M. C., Gross, L. A., Ravindran, A., ... Ronco, P. (2019). Exostosin 1/Exostosin 2-Associated Membranous Nephropathy. Journal of the American Society of Nephrology : JASN, 30(6), 1123-1136. https://doi.org/10.1681/ASN.2018080852

Exostosin 1/Exostosin 2-Associated Membranous Nephropathy. / Sethi, Sanjeev M; Madden, Benjamin J.; Debiec, Hanna; Charlesworth, M. Cristine; Gross, Lou Ann; Ravindran, Aishwarya; Hummel, Amber M.; Specks, Ulrich; Fervenza, Fernando Custodio; Ronco, Pierre.

In: Journal of the American Society of Nephrology : JASN, Vol. 30, No. 6, 01.06.2019, p. 1123-1136.

Research output: Contribution to journalArticle

Sethi, SM, Madden, BJ, Debiec, H, Charlesworth, MC, Gross, LA, Ravindran, A, Hummel, AM, Specks, U, Fervenza, FC & Ronco, P 2019, 'Exostosin 1/Exostosin 2-Associated Membranous Nephropathy', Journal of the American Society of Nephrology : JASN, vol. 30, no. 6, pp. 1123-1136. https://doi.org/10.1681/ASN.2018080852
Sethi, Sanjeev M ; Madden, Benjamin J. ; Debiec, Hanna ; Charlesworth, M. Cristine ; Gross, Lou Ann ; Ravindran, Aishwarya ; Hummel, Amber M. ; Specks, Ulrich ; Fervenza, Fernando Custodio ; Ronco, Pierre. / Exostosin 1/Exostosin 2-Associated Membranous Nephropathy. In: Journal of the American Society of Nephrology : JASN. 2019 ; Vol. 30, No. 6. pp. 1123-1136.
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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.",
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T1 - Exostosin 1/Exostosin 2-Associated Membranous Nephropathy

AU - Sethi, Sanjeev M

AU - Madden, Benjamin J.

AU - Debiec, Hanna

AU - Charlesworth, M. Cristine

AU - Gross, Lou Ann

AU - Ravindran, Aishwarya

AU - Hummel, Amber M.

AU - Specks, Ulrich

AU - Fervenza, Fernando Custodio

AU - Ronco, Pierre

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N2 - 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.

AB - 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.

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