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Abstract: PO1467

Hematopoietic Stem Cell Transplant Membranous Nephropathy Is Associated with Protocadherin FAT1

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Sethi, Sanjeev, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Madden, Benjamin J., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Nasr, Samih H., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Fervenza, Fernando C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Haas, Mark, Cedars-Sinai Medical Center, Los Angeles, California, United States
Background

Membranous nephropathy (MN) is a common cause of proteinuria in patients with a hematopoietic stem cell transplant (HSCT). The antigen(s) responsible for MN in HSCT-associated MN is unknown.

Methods

We performed laser microdissection and mass spectrometry (MS/MS) of glomeruli of 230 cases of PLA2R-negative MN to detect novel proteins/antigens in MN. These included PLA2R-negative MN developing in the setting of HSCT and de-novo MN in the kidney transplant.

Results

We detected a novel protein Protocadherin FAT1 (FAT1) in 9 cases of PLA2R-negative MN. Of the 9 FAT1-associated MN cases, 7 patients followed HSCT and 2 followed kidney transplant (de-novo MN). HSCT was done for treatment of AML (5 cases), MDS (1 case) and essential thrombocytopenia (1 case). All 9 cases were negative for known antigens of MN including PLA2R, THSD7A, NELL1, PCDH7, NCAM1, SEMA3B and HTRA1. Baseline PLA2R spectral counts were detected in 7 of the 9 cases. The FAT1 total spectral counts ranged from 27 to 70 (mean 44.1 ± 13.1). FAT1 was not detected by MS/MS in 115 control cases that included time 0 transplant, minimal change disease, FSGS, diabetes and IgA nephropathy. FAT1 was also not detected in 28 cases of PLA2R-positive MN. No case of FAT1-associated MN was detected in a non-transplant setting. The mean age of patients with FAT1-associated MN was 56 ± 9.7 yrs, 7 patients were females and 2 were males. MN occurred 2.5 ± 0.8 yrs and 7.5 ± 1.2 yrs after HSCT and kidney transplant, respectively. The mean serum creatinine and proteinuria at kidney biopsy was 1.9 ± 1.2 mg/dL and 7.4 ± 5.4 gms/L, respectively. Kidney biopsy showed IgG (2-3+) and minimal C3 (0-1+) along glomerular capillary walls; electron microscopy showed stage II MN in 8 out of 9 cases.

Conclusion

FAT1 appears to be a unique protein found in MN developing in the setting of HSCT and de-novo MN following kidney transplant. Further studies to localize FAT1 on the glomerular basement membranes and detect circulating antibodies are ongoing.

Proteomic identification of FAT1 in 9 cases of PLA2R-negative MN. All 9 cases show large spectral counts of FAT1 and only baseline spectral counts of PLA2R. Case 3 and 5 are de-novo MN in kidney transplant, the remaining are following HSCT.