Hematopoietic Stem Cell Transplant-Membranous Nephropathy Is Associated with Protocadherin FAT1

Sanjeev Sethi, Benjamin Madden, Marta Casal Moura, Samih H. Nasr, Nattawat Klomjit, Lou Ann Gross, Vivian Negron, M. Cristine Charlesworth, Mariam P. Alexander, Nelson Leung, Ulrich Specks, Fernando C. Fervenza, Mark Haas

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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 languageEnglish (US)
Pages (from-to)1033-1044
Number of pages12
JournalJournal of the American Society of Nephrology
Volume33
Issue number5
DOIs
StatePublished - 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

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