Familial Fibrillary Glomerulonephritis in Living Related Kidney Transplantation

Jeyabalan, Anushya; Batal, Ibrahim; Piras, Doloretta; Morris, Heather; Appel, Gerald B.

doi:10.1016/j.ekir.2020.10.022

Cited by 5 publications

(9 citation statements)

References 9 publications

(5 reference statements)

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“…Familial FGN is rare (<1% of cases), reported in 6 families [32][33][34][35]. Gene sequencing in 4 patients (including whole-exome sequencing in one familial FGN) [32] has not revealed pathogenic mutations in DNAJB9 [10]. These familial studies -although small -and the presence of full-length DNAJB9 protein in deposits suggest that pathogenesis is not driven by DNAJB9 mutations.…”

Section: Genetic Associations Of Fgnmentioning

confidence: 83%

“…The identification of rare cases of DNAJB9-positive but immunoglobulin-negative FGN [44] however suggests that DNAJB9 is the initiator of disease, but, circulating anti-DNAJB9 antibodies have not yet been identified. The presence of full-length DNAJB9 protein in immune deposits [9,10] and lack of DNAJB9 mutations in a few tested patients [10,32] provide evidence against a genetically mutant form of DNAJB9 as a driver of FGN, although posttranscriptional or epigenetic modifications are possible.…”

Section: Proposed Pathogenic Mechanisms Of Fgnmentioning

confidence: 99%

Section: Genetic Associations Of Fgnmentioning

confidence: 99%

“…The slower progression of FGN in allografts may be due to earlier detection with protocol biopsies, immunosuppression, or other factors. Intriguingly, reports of nearly asymptomatic FGN in the allograft [58][59][60] and native [32] kidney raise the possibility that the FGN may be a slowly progressive disease that is frequently diagnosed upon the onset of clinical symptoms, late in the disease course.…”

Section: Transplant In Fgnmentioning

confidence: 99%

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Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response

et al. 2022

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Background: Fibrillary glomerulonephritis (FGN) is found in approximately 1% of native kidney biopsies and was traditionally defined by glomerular deposition of fibrils larger than amyloid (12-24nm diameter) composed of polyclonal IgG. Recent identification of DNAJB9 as a sensitive and specific marker of FGN has revolutionized FGN diagnosis and opened new avenues to studying FGN pathogenesis. In this review, we synthesize recent literature to provide an updated appraisal of the clinical and pathologic features of FGN, discuss diagnostic challenges and pitfalls, and propose molecular models of disease in light of DNAJB9. Summary: DNAJB9 tissue assays, paraffin immunofluorescence studies, and IgG subclass testing demonstrate that FGN is distinct from other glomerular diseases with organized deposits and highlight FGN morphologic variants. Additionally, these newer techniques show that FGN is only rarely monoclonal, and patients with monoclonal FGN usually do not have a monoclonal gammopathy. DNAJB9 mutation does not appear to affect the genetic architecture of FGN, however, the accumulation of DNAJB9 in FGN deposits suggests that disease is driven, at least in part, by proteins involved in the unfolded protein response. Treatments for FGN remains empiric, with some encouraging data suggesting that rituximab-based therapy is effective and that transplantation is a good option for patients progressing to ESKD. Key Messages: DNAJB9 aids in distinguishing FGN from other glomerular diseases with organized deposits. Further investigations into the role of DNAJB9 in FGN pathogenesis are necessary to better understand disease initiation and progression, and to ultimately develop targeted therapies.

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Section: Genetic Associations Of Fgnmentioning

confidence: 83%

Section: Proposed Pathogenic Mechanisms Of Fgnmentioning

confidence: 99%

Section: Genetic Associations Of Fgnmentioning

confidence: 99%

Section: Transplant In Fgnmentioning

confidence: 99%

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Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response

et al. 2022

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“…Being a rare entity, comprising only 0.5%–1% of native kidney biopsies ( 2 ), FGN has a great variety in terms of its etiology, clinical manifestations, and light microscopic appearance ( 3 ). Although FGN is mostly acquired, the presence of familiar FGN has also been recognized lately ( 4 , 5 ). The renal prognosis is generally poor, with nearly half of the patients progressing to end-stage renal disease within 4 years ( 6 ).…”

mentioning

confidence: 99%

Fibrillary Glomerulonephritis and Monoclonal Gammopathy: Potential Diagnostic Challenges

Goh

Lau

et al. 2022

Front. Oncol.

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Fibrillary glomerulonephritis (FGN) is a rare glomerular disease featured by the randomly arranged 12- to 24-nm fibrils under electron microscopy (EM). Up to 10% of FGN patients have monoclonal gammopathy. However, distinguishing between FGN as monoclonal gammopathy of renal significance (MGRS) and FGN from other causes with incidental monoclonal gammopathy of undetermined significance (MGUS) can be challenging, as the current way of demonstrating monoclonality is flawed due to (1) the suboptimal sensitivity of kappa staining by immunofluorescence in frozen tissue (IF-F) as compared to pronase-digested paraffin sections (IF-P), causing incorrect labeling of light chain restriction; (2) the unavailability of immunoglobulin G (IgG) subtyping in some centers; and (3) the unavailability of tests demonstrating the monoclonality of highly variable VH or VL domains in immunoglobulin structures in clinical use. The discovery of DnaJ homolog subfamily B member 9 (DNAJB9) allows diagnosis for FGN with less reliance on EM, and the summary of recent studies revealed that genuine MGRS is extremely rare among FGN. Further research integrating IF-P, IgG subtyping, VH or VL domain monoclonality confirmation, and DNAJB9 as diagnostic modalities, with corresponding clinical data including treatment response and prognosis, is required for a better understanding of this subject.

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