TY - JOUR
T1 - Protocadherin 7-associated membranous nephropathy
AU - Sethi, Sanjeev
AU - Madden, Benjamin
AU - Debiec, Hanna
AU - Morelle, Johann
AU - Charlesworth, M. Cristine
AU - Gross, Lou Ann
AU - Negron, Vivian
AU - Buob, David
AU - Chaudhry, Sidharth
AU - Jadoul, Michel
AU - Fervenza, Fernando C.
AU - Ronco, Pierre
N1 - Funding Information:
F.C. Fervenza reports consultancy agreements with Alexion Pharmaceuticals, Alnylam, ByoCrystal, Novartis, and Takeda; research funding from Che-mocentryx, Genentech, Janssen Pharmaceutical, Questcor/Mallinckrodt, and Retrophin; honoraria from UpToDate; and scientific advisor or membership with JASN, Kidney International, Nephrology, Nephrology Dialysis and Transplantation, and UpToDate. M. Jadoul reports consultancy agreements with Amgen, Astellas, Astra-Zeneca, Boehringer-Ingelheim, Fresenius Medical Care Renal Pharma, MSD, Mundipharma, and Vifor; research funding from Amgen, MSD, Otsuka, and Roche; honoraria from Amgen, Astellas, Boehringer-Ingelheim, Menarini, MSD, and Vifor Fresenius Medical Care Renal Pharma; scientific advisor or membership as theme editor of Nephrology Dialysis and Transplantation; speakers bureau with Amgen, Astra-Zeneca, Me-narini, MSD, Mundipharma, and Vifor Fresenius Medical Care Renal Pharma; and other interests/relationships as cochair of Kidney Disease Improving Global Outcomes 2019. J. Morelle reports research funding from Alexion Pharmaceuticals; scientific advisor or membership with AstraZeneca and Ver-santis; speakers bureau with Baxter HealthCare and Fresenius Medical Care; and other interests/relationships with the Association pour l’Information et la Recherche sur les Maladies Rénales Génétiques (Brussels, Belgium), the National Fund for Scientific Research (Fonds de la Recherche Scientifique-Fonds National de la Recherche Scientifique, Brussels, Belgium), the Saint-Luc Foundation (Brussels, Belgium), and Sanofi-Genzyme (travel grant). P. Ronco reports consultancy agreements with Alexion, Amicus, Morphosys, and Otsuka; research funding from Alexion and Amgen; honoraria from Amicus and Morphosys; and scientific advisor or membership with Amicus and Morphosys. S. Sethi reports honoraria from teaching, grand rounds, lectures, UpToDate, and reviewing slides for a study for Novartis. All remaining authors have nothing to disclose.
Funding Information:
J. Morelle is supported by Fonds National pour la Recherche Scientifique grants 40000157 and 4003771, the Fondation Saint-Luc, the Fonds de Recherche Clinique des Cliniques universitaires Saint-Luc, and the Association pour l’Information et la Recherche sur les maladies rénales Génétiques. P. Ronco is a recipient of European Research Council European Research Council-2012-ADG_20120314 grant 322947, Seventh Framework Programme of the European Community contract 2012-305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases), and National Research Agency grants Membranous Nephropathy aims (ANR-17-CE17-0012-01) and SeroNegative Membranous Nephropathy (ANR-20-CE17-0017-01).
Publisher Copyright:
© 2021 by the American Society of Nephrology
PY - 2021/5
Y1 - 2021/5
N2 - Background Membranous nephropathy (MN) results from deposition of antigen-antibody complexes along the glomerular basement membrane (GBM). PLA2R, THSD7A, NELL1, and SEMA3B account for 80%-90% of target antigens in MN. Methods We performed laser microdissection and mass spectrometry (MS/MS) in kidney biopsies from 135 individuals with PLA2R-negative MN, and used immunohistochemistry/immunofluorescence and confocal microscopy to confirm the MS/MS finding, detect additional cases, and localize the novel protein. We also performed MS/MS and immunohistochemistry on 116 controls and used immunofluorescence microscopy to screen biopsy samples from two validation cohorts. Western blot and elution studies were performed to detect antibodies in serum and biopsy tissue. Results MS/MS studies detected a unique protein, protocadherin 7 (PCDH7), in glomeruli of ten (5.7%) PLA2R-negative MN cases, which also were negative for PLA2R, THSD7A, EXT1/EXT2, NELL1, and SEMA3B. Spectral counts ranged from six to 24 (average 13.2 [SD 6.6]). MS/MS did not detect PCDH7 in controls (which included 28 PLA2R-positive cases). In all ten PCDH7-positive cases, immunohistochemistry showed bright granular staining along the GBM, which was absent in the remaining cases of PLA2Rnegative MN and control cases. Four of 69 (5.8%) cases in the validation cohorts (all of which were negative for PLA2R, THSD7A, EXT1, NELL1, and SEMA3B) were PCDH7-positive MN. Kidney biopsy showed minimal complement deposition in 12 of the 14 PCDH7-associated cases. Confocal microscopy showed colocalization of PCDH7 and IgG along the GBM. Western blot analysis using sera from six patients showed antibodies to nonreduced PCDH7. Elution of IgG from frozen tissue of PCDH7-associated MN showed reactivity against PCDH7. Conclusions MN associated with the protocadherin PCDH7 appears to be a distinct, previously unidentified type of MN.
AB - Background Membranous nephropathy (MN) results from deposition of antigen-antibody complexes along the glomerular basement membrane (GBM). PLA2R, THSD7A, NELL1, and SEMA3B account for 80%-90% of target antigens in MN. Methods We performed laser microdissection and mass spectrometry (MS/MS) in kidney biopsies from 135 individuals with PLA2R-negative MN, and used immunohistochemistry/immunofluorescence and confocal microscopy to confirm the MS/MS finding, detect additional cases, and localize the novel protein. We also performed MS/MS and immunohistochemistry on 116 controls and used immunofluorescence microscopy to screen biopsy samples from two validation cohorts. Western blot and elution studies were performed to detect antibodies in serum and biopsy tissue. Results MS/MS studies detected a unique protein, protocadherin 7 (PCDH7), in glomeruli of ten (5.7%) PLA2R-negative MN cases, which also were negative for PLA2R, THSD7A, EXT1/EXT2, NELL1, and SEMA3B. Spectral counts ranged from six to 24 (average 13.2 [SD 6.6]). MS/MS did not detect PCDH7 in controls (which included 28 PLA2R-positive cases). In all ten PCDH7-positive cases, immunohistochemistry showed bright granular staining along the GBM, which was absent in the remaining cases of PLA2Rnegative MN and control cases. Four of 69 (5.8%) cases in the validation cohorts (all of which were negative for PLA2R, THSD7A, EXT1, NELL1, and SEMA3B) were PCDH7-positive MN. Kidney biopsy showed minimal complement deposition in 12 of the 14 PCDH7-associated cases. Confocal microscopy showed colocalization of PCDH7 and IgG along the GBM. Western blot analysis using sera from six patients showed antibodies to nonreduced PCDH7. Elution of IgG from frozen tissue of PCDH7-associated MN showed reactivity against PCDH7. Conclusions MN associated with the protocadherin PCDH7 appears to be a distinct, previously unidentified type of MN.
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U2 - 10.1681/ASN.2020081165
DO - 10.1681/ASN.2020081165
M3 - Article
C2 - 33833079
AN - SCOPUS:85105186167
VL - 32
SP - 1249
EP - 1261
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
SN - 1046-6673
IS - 5
ER -