Fibrillary glomerulonephritis or complement 3 glomerulopathy: a rare case of diffuse necrotising crescentic glomerulonephritis with C3-dominant glomerular deposition and positive DNAJB9

Baker, Lyle W.; Khan, Mahnoor; Cortese, Cherise; Aslam, Nabeel

doi:10.1136/bcr-2020-239868

Cited by 5 publications

(4 citation statements)

References 16 publications

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“…HSP40 is reported as a biomarker of fibrillary glomerulonephritis, which is an autoimmune disease characterized by the extracellular deposition of nonamyloid fibrils 213 . DNAJB9, a member in HSP40 family, colocalizes with the fibrils, 214 indicating that HSP40 causes an immunostimulatory response in this context. In atherosclerosis, HDJ‐2, a homolog of human HSP40 found in E. coli , is highly expressed in atheromatous lesions, which may play an important role in T‐cell activation in the development of atherosclerosis 215 .…”

Section: Heat Shock Proteins In Diseasesmentioning

confidence: 99%

Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities

Yang

Zhou

et al. 2022

MedComm

261

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The heat shock proteins (HSPs) are ubiquitous and conserved protein families in both prokaryotic and eukaryotic organisms, and they maintain cellular proteostasis and protect cells from stresses. HSP protein families are classified based on their molecular weights, mainly including large HSPs, HSP90, HSP70, HSP60, HSP40, and small HSPs. They function as molecular chaperons in cells and work as an integrated network, participating in the folding of newly synthesized polypeptides, refolding metastable proteins, protein complex assembly, dissociating protein aggregate dissociation, and the degradation of misfolded proteins. In addition to their chaperone functions, they also play important roles in cell signaling transduction, cell cycle, and apoptosis regulation. Therefore, malfunction of HSPs is related with many diseases, including cancers, neurodegeneration, and other diseases. In this review, we describe the current understandings about the molecular mechanisms of the major HSP families including HSP90/HSP70/HSP60/HSP110 and small HSPs, how the HSPs keep the protein proteostasis and response to stresses, and we also discuss their roles in diseases and the recent exploration of HSP related therapy and diagnosis to modulate diseases. These research advances offer new prospects of HSPs as potential targets for therapeutic intervention.

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Section: Heat Shock Proteins In Diseasesmentioning

confidence: 99%

Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities

Yang

Zhou

et al. 2022

MedComm

261

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“…Cases with ambiguous histopathological features or multiple concurrent diseases in association to FGN are rare, but can occur [ 3 , 23 ]. Our series presented four cases that originally presented ambiguous features using conventional (i.e., without DNAJB9 IHC) diagnostic workup and four cases with concurrent disease.…”

Section: Discussionmentioning

confidence: 99%

DNAJB9 Is a Reliable Immunohistochemical Marker of Fibrillary Glomerulonephritis: Evaluation of Diagnostic Efficacy in a Large Series of Kidney Biopsies

et al. 2022

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Fibrillary glomerulonephritis (FGN) is a rare glomerular disease characterized by a challenging diagnostic workup requiring ultrastructural identification of 20 nm-thick randomly oriented fibrillar deposits. However, the recent introduction of DNAJB9 as a putative diagnostic marker of FGN could thoroughly improve this diagnostic scenario. This study aims to assess the DNAJB9 immunohistochemical expression in a large series of FGN cases and to eventually confirm its role as a diagnostic marker of FGN. We evaluated the immunohistochemical expression of DNAJB9 (Rabbit Polyclonal, ThermoFisher) in a series of 77 FGN and 128 non-FGN cases diagnosed between January 1992 and June 2022 at the Pathology Unit of the AOU Città della Salute e della Scienza Hospital. DNAJB9 was expressed in 73 of the 74 evaluable FGN cases, mostly showing a strong glomerular positivity (68 cases). Additionally, DNAJB9 resulted positive in all challenging scenarios [early-stage (6), congophilic (4), combined (4), and uncertain (4) cases of FGN)]. DNAJB9 was negative in all non-FGN cases, eventually resulting in a specificity of 100% and sensitivity of 99%. In conclusion, we confirmed the role of DNAJB9 as a diagnostic marker of FGN. Its adoption in the clinical routine will allow a faster, more feasible, and more accurate FGN diagnosis.

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“…Immunoglobulin-negative FGN was described in a multi-institutional cohort of 9 cases of a fibrillar GN with DNAJB9 expression which appear to lack IgG by frozen and paraffin IF and mass spectrometry [44]; the presence of IgG heavy and light chains had previously been considered a defining feature of FGN [7,[44][45][46]. Scant IgG staining with prominent C3 deposits and crescents has also been described [47]. The presence of DNAJB9 and lack of substantial IgG in these rare cases suggest that DNAJB9, not IgG, could be the major player in initial fi- bril formation, a mechanistic distinction with potential therapeutic implications [44].…”

Section: Histologic Variants Of Fgnmentioning

confidence: 99%

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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Fibrillary glomerulonephritis or complement 3 glomerulopathy: a rare case of diffuse necrotising crescentic glomerulonephritis with C3-dominant glomerular deposition and positive DNAJB9

Cited by 5 publications

References 16 publications

Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities

Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities

DNAJB9 Is a Reliable Immunohistochemical Marker of Fibrillary Glomerulonephritis: Evaluation of Diagnostic Efficacy in a Large Series of Kidney Biopsies

Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response

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