Hematopoietic Stem Cell Transplant-M embranous Nephropathy Is Associated with Protocadherin FAT1

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.& nbsp;Methods We performed laser microdissection and tandem mass spectrometry (MS/MS) of glomeruli from250 patients with PLA2R-negative MN to detect novel antigens in MN. This was followed by immunohis to-chemical (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'.& nbsp;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 i n 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 FAT1ranged 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 (0to11) along the GBM; IgG4 was the dominant IgG subclass. IHCafter 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.& nbsp;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.& nbsp;

Automated summary

In this study, a novel antigen associated with membranous nephropathy (MN) in patients receiving hematopoietic stem cell transplant (HSCT) was identified using laser microdissection and tandem mass spectrometry (MS/MS). The antigen, called FAT1, was detected in the glomeruli of patients with PLA2R-negative MN. Further studies confirmed the presence of FAT1-associated MN in a majority of HSCT-related MN cases. This study provides valuable insights into the pathogenesis of MN in HSCT patients and may contribute to the development of targeted therapies.