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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 of 250 cases of PLA2R-negative MN to detect novel antigens in MN. This was followed by immunohistochemical (IHC)/immunofluorescence microscopy (IF) studies to localize the novel antigen. Western blot analyses were performed using serum and IgG eluted from frozen biopsy tissue to demonstrate IgG binding to the antigen. Results: MS/MS detected a novel protein, protocadherin FAT1 (FAT1), in 9 cases of PLA2R-negative MN. All 9 MN cases developed following allogeneic HSCT (Mayo Clinic discovery cohort). Next, we performed MS/MS in 5 known cases of allogeneic HSCT-associated MN (Cedar Sinai validation cohort). FAT1 was detected in all 5 cases by MS/MS. The total spectral counts for FAT1 ranged from 8 to 39 (mean 20.9 ± 10.1). All 14 cases were negative for known antigens of MN, including PLA2R, THSD7A, NELL1, PCDH7, NCAM1, SEMA3B, and HTRA1. Kidney biopsy showed IgG (2-3+) with mild C3 (0-1+) along the GBM; IgG4 was the dominant IgG subclass. IHC following 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 FAT1-asssociated MN, but not from 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.

BackgroundLittle is known about the rate and predictors of finding lesions of monoclonal gammopathy (MG) of renal significance (MGRS) on kidney biopsy specimens among patients with MG.MethodsWe reviewed the medical records from 2013 to 2018 at the Mayo Clinic in Rochester, Minnesota, to identify patients with MG and whether they had undergone a kidney biopsy. In a more select group of patients with MG from 2017 to 2018, we conducted a review of records to determine how many had underlying CKD, which of those with CKD had undergone a kidney biopsy, and reasons for deferring a kidney biopsy.ResultsBetween 2013 and 2018, we identified 6300 patients who had MG, 160 (2.5%) of whom had undergone a kidney biopsy. Of the 160 patients, 64 (40%) had an MGRS lesion; amyloid light chain amyloidosis, the most common finding, accounted for nearly half of these lesions. In the non-MGRS group comprising 96 patients, 23 had arteriosclerosis, the most common finding. In multivariate analysis, strong predictors of finding an MGRS lesion included the presence of an elevated free light chain ratio, proteinuria, and hematuria. Among 596 patients with CKD and MG from 2017 to 2018, 62 (10.4%) underwent a kidney biopsy. Kidney biopsy was deferred for 70 patients (20%); for 62 of the 70, the diagnosis was already known, and eight were not candidates for therapy. Younger age and higher proteinuria and serum creatinine levels increased the likelihood that the patient would undergo a kidney biopsy.ConclusionsProteinuria ≥1.5 g/d, hematuria, and an elevated free light chain ratio increase the likelihood of finding MGRS, and a kidney biopsy should be highly considered in such patients.

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Fibrillary GN (FGN) is a rare glomerular disease that is diagnosed based on the presence of fibrils in glomeruli. The fibrils are typically noncongophilic, randomly oriented, and measure 12–24 nm. Traditionally, electron microscopy (EM) has been an important tool to aid in the diagnosis of FGN by identifying the fibrils and to distinguish it from other entities that could mimic FGN. However, recently DnaJ homolog subfamily B member 9 (DNAJB9) has emerged as both a specific and sensitive biomarker in patients with FGN. It allows prompt diagnosis and alleviates reliance on EM. DNAJB9 is a cochaperone of heat shock protein 70 and is involved in endoplasmic reticulum protein-folding pathways. But its role in the pathogenesis of FGN remains elusive. DNAJB9 may act as a putative antigen or alternatively it may secondarily bind to misfolded IgG in the glomeruli. These hypotheses need future studies to elucidate the role of DNAJB9 in the pathogenesis of FGN. The treatment regimen for FGN has been limited due to paucity of studies. Most patients receive combination immunosuppressive regimens. Rituximab has been studied the most in FGN and it may delay disease progression. Prognosis of FGN remains poor and 50% require dialysis within 2 years of diagnosis. Despite its poor prognosis in native kidneys, the rate of recurrence post-transplantation is low (20%) and patient as well as allograft outcomes are similar to patients without FGN.