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Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response

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 (12–24 nm diameter) composed of polyclonal IgG. Recent identification of DNAJB9 as a sensitive and specific mar...

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Autores principales: Andeen, Nicole K., Kung, Vanderlene L., Robertson, Josh, Gurley, Susan B., Avasare, Rupali S., Sitaraman, Sneha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: S. Karger AG 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9936766/
https://www.ncbi.nlm.nih.gov/pubmed/36817290
http://dx.doi.org/10.1159/000525542
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author Andeen, Nicole K.
Kung, Vanderlene L.
Robertson, Josh
Gurley, Susan B.
Avasare, Rupali S.
Sitaraman, Sneha
author_facet Andeen, Nicole K.
Kung, Vanderlene L.
Robertson, Josh
Gurley, Susan B.
Avasare, Rupali S.
Sitaraman, Sneha
author_sort Andeen, Nicole K.
collection PubMed
description 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 (12–24 nm 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 remain 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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spelling pubmed-99367662023-02-18 Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response Andeen, Nicole K. Kung, Vanderlene L. Robertson, Josh Gurley, Susan B. Avasare, Rupali S. Sitaraman, Sneha Glomerular Dis Review Article 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 (12–24 nm 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 remain 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. S. Karger AG 2022-06-16 /pmc/articles/PMC9936766/ /pubmed/36817290 http://dx.doi.org/10.1159/000525542 Text en Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel https://creativecommons.org/licenses/by-nc/4.0/This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission.
spellingShingle Review Article
Andeen, Nicole K.
Kung, Vanderlene L.
Robertson, Josh
Gurley, Susan B.
Avasare, Rupali S.
Sitaraman, Sneha
Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response
title Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response
title_full Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response
title_fullStr Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response
title_full_unstemmed Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response
title_short Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response
title_sort fibrillary glomerulonephritis, dnajb9, and the unfolded protein response
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9936766/
https://www.ncbi.nlm.nih.gov/pubmed/36817290
http://dx.doi.org/10.1159/000525542
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