Abstract
BACKGROUND: Membranous nephropathy (MN) is a common cause of proteinuria in patients receiving a hematopoietic stem cell transplant (HSCT). The target antigen in HSCT-associated MN is unknown.
METHODS: We performed laser microdissection and tandem mass spectrometry (MS/MS) of glomeruli from 250 patients with PLA2R-negative MN to detect novel antigens in MN. This was followed by immunohistochemical (IHC)/immunofluorescence (IF) microscopy studies to localize the novel antigen. Western blot analyses using serum and IgG eluted from frozen biopsy specimen to detect binding of IgG to new 'antigen'.
RESULTS: MS/MS detected a novel protein, protocadherin FAT1 (FAT1), in nine patients with PLA2R-negative MN. In all nine patients, MN developed after allogeneic HSCT (Mayo Clinic discovery cohort). Next, we performed MS/MS in five patients known to have allogeneic HSCT-associated MN (Cedar Sinai validation cohort). FAT1 was detected in all five patients by MS/MS. The total spectral counts for FAT1 ranged from 8 to 39 (mean±SD, 20.9±10.1). All 14 patients were negative for known antigens of MN, including PLA2R, THSD7A, NELL1, PCDH7, NCAM1, SEMA3B, and HTRA1. Kidney biopsy specimens showed IgG (2 to 3+) with mild C3 (0 to 1+) along the GBM; IgG4 was the dominant IgG subclass. IHC after protease digestion and confocal IF confirmed granular FAT1 deposits along the GBM. Lastly, Western blot analyses detected anti-FAT1 IgG and IgG4 in the eluate obtained from pooled frozen kidney biopsy tissue and in the serum of those with FAT1-asssociated MN, but not from those with PLA2R-associated MN.
CONCLUSIONS: FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents a majority of MN associated with HSCT.
Original language | English (US) |
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Pages (from-to) | 1033-1044 |
Number of pages | 12 |
Journal | Journal of the American Society of Nephrology |
Volume | 33 |
Issue number | 5 |
DOIs | |
State | Published - May 2022 |
Bibliographical note
Funding Information:F.C. Fervenza reports having consultancy agreements with Alexion Pharmaceuticals, Alnylam, ByoCrystal, Novartis, and Takeda; receiving research funding from Chemocentryx, Genentech, Janssen Pharmaceutical, Questcor/Mallinckrodt, and Retrophin; serving in an advisory or leadership role for JASN, Kidney International, Nephrology, Nephrology Dialysis and Transplantation, and UpToDate; and receiving honoraria from UpTo-Date. M. Haas reports having consultancy agreements with Argenx, Astra-Zeneca, CareDx, Novartis, Retrophin, and Shire Viropharma Inc.; serving in an advisory or leadership role for Argenx, CareDx, Novartis, and Retro-phin; and receiving honoraria from, and serving on a speakers bureau for, CareDx. N. Leung reports having consultancy agreements with AbbVie, Lilly, and Omeros; receiving research funding from Alnylam and Omeros; having other interests in, or relationships with, Amyloidosis Research Consortium; having ownership interest in Checkpoint Therapeutics; and serving in an advisory or leadership role for Journal of Nephrology. S. Sethi reports receiving honoraria for teaching, conducting grand rounds, giving lectures, reviewing slides for a study for Novartis, and from UpToDate. U. Specks reports having ownership interest in AbbVie, Johnson & Johnson, Pfizer, and Viatris; receiving research funding from AstraZeneca, Boehringer Ingelheim, Bristol Myer Squibb, Genentech, and GlaxoSmithKline; having consultancy agreements with AstraZeneca and ChemoCentryx; and having patents with, or receiving royalties from, Mayo Foundation for Education and Research and UpToDate. All remaining authors have nothing to disclose.
Publisher Copyright:
© 2022 by the American Society of Nephrology.
Keywords
- Autoantibodies
- Cadherins
- Female
- Glomerulonephritis, Membranous
- Hematopoietic Stem Cell Transplantation/adverse effects
- High-Temperature Requirement A Serine Peptidase 1
- Humans
- Immunoglobulin G
- Male
- Protocadherins
- Receptors, Phospholipase A2
- Tandem Mass Spectrometry
PubMed: MeSH publication types
- Journal Article