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


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 PLA2Rnegative 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 (mean6SD, 20.9610.1). 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 31) with mild C3 (0 to 11) 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 PLA2Rassociated MN. Conclusions FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1- associated MN represents a majority ofMN associated with HSCT.

Original languageEnglish (US)
Pages (from-to)1033-1044
Number of pages12
JournalJournal of the American Society of Nephrology
Issue number5
StatePublished - May 2022

ASJC Scopus subject areas

  • Nephrology


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