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Kidney Int. 2020 Jan;97(1):163-174. doi: 10.1016/j.kint.2019.09.014. Epub 2019 Oct 7.

Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy.

Author information

1
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address: sethi.sanjeev@mayo.edu.
2
Sorbonne Université, Université Pierre et Marie Curie Paris 06, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, Paris, France.
3
Medical Genome Facility, Proteomics Core, Mayo Clinic, Rochester, Minnesota, USA.
4
Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
5
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
6
Sorbonne Université, Université Pierre et Marie Curie Paris 06, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, Paris, France; Department of Pathology, Tenon Hospital, Paris, France.
7
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
8
Sorbonne Université, Université Pierre et Marie Curie Paris 06, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, Paris, France; Hôpital de Jour-Nephrology, Assistance Publique-Hôpitaux de Paris, Paris, France.

Abstract

Membranous nephropathy is characterized by deposition of immune complexes along the glomerular basement membrane. PLA2R and THSD7A are target antigens in 70% and 1-5% of primary membranous nephropathy cases, respectively. In the remaining cases, the target antigen is unknown. Here, laser microdissection of glomeruli followed by mass spectrometry was used to identify novel antigen(s) in PLA2R-negative membranous nephropathy. An initial pilot mass spectrometry study in 35 cases of PLA2R-negative membranous nephropathy showed high spectral counts for neural tissue encoding protein with EGF-like repeats, NELL-1, in six cases. Mass spectrometry failed to detect NELL-1 in 23 PLA2R-associated membranous nephropathy and 88 controls. NELL-1 was localized by immunohistochemistry, which showed bright granular glomerular basement membrane staining for NELL-1 in all six cases. Next, an additional 23 NELL-1 positive cases of membranous nephropathy were identified by immunohistochemistry in a discovery cohort of 91 PLA2R-negative membranous nephropathy cases, 14 were confirmed by mass spectrometry. Thus, 29 of 126 PLA2R-negative cases were positive for NELL-1. PLA2R-associated membranous nephropathy and controls stained negative for NELL-1. We then identified five NELL-1 positive cases of membranous nephropathy out of 84 PLA2R and THSD7A-negative cases in two validation cohorts from France and Belgium. By confocal microscopy, both IgG and NELL-1 co-localized to the glomerular basement membrane. Western blot analysis showed reactivity to NELL-1 in five available sera, but no reactivity in control sera. Clinical and biopsy findings of NELL-1 positive membranous nephropathy showed features of primary membranous nephropathy. Thus, a subset of membranous nephropathy is associated with accumulation and co-localization of NELL-1 and IgG along the glomerular basement membrane, and with anti-NELL-1 antibodies in the serum. Hence, NELL-1 defines a distinct type of primary membranous nephropathy.

KEYWORDS:

NELL-1; mass spectrometry; membranous nephropathy

PMID:
31901340
DOI:
10.1016/j.kint.2019.09.014
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