Clinicopathologic features and treatment outcomes of patients with fibrillary glomerulonephritis

Marinaki, Smaragdi; Tsiakas, Stathis; Liapis, George; Skalioti, Chrysanthi; Kapsia, Eleni; Lionaki, Sophia; Boletis, John

doi:10.1097/md.0000000000026022

Cited by 6 publications

(4 citation statements)

References 23 publications

(89 reference statements)

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“…Patients with FGN classically present in middle age (average 49-61 years) with decreased kidney function (average serum creatinine 2.1-3.7 mg/dL), microscopic hematuria (in 39-95%), and proteinuria (average 4.1-7.3 g/day) and occasionally frank nephrotic syndrome (in 15-52%) [3-8, 11, 12, 15, 16]. Approximately 41-74% of FGN patients are female, with a female predominance in US-based cohorts (female-to-male ratio 1.2-2.8:1) [12] and a male predominance reported in studies from France, Switzerland, and Greece [15][16][17]. FGN is rarely found in young adults [18,19].…”

Section: Clinical Associations 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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Section: Clinical Associations Of Fgnmentioning

confidence: 99%

Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response

et al. 2022

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“…These effects lead to loss of DNA expression, cell cycle arrest, inhibition of replication, and, ultimately, death often via apoptosis. The rationale for use of these agents in the treatment of GD is inhibition of immune cell development and function resulting in strong immunosuppression [ 44 ]. Two commonly used alkylating agents in GD are cyclophosphamide (CYP) and chlorambucil.…”

Section: Sars-cov-2 Vaccines In Context Of Immunosuppression Therapymentioning

confidence: 99%

Immunosuppression in Glomerular Diseases: Implications for SARS-CoV-2 Vaccines and COVID-19

Yeaman

2021

Glomerular Dis

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Background: Glomerular diseases (GD) are chronic conditions that often involve immune dysfunction and require immunosuppressive therapy (IST) to control underlying pathogenesis. Unfortunately, such diseases appear to heighten risks of severe outcomes in COVID-19 and predispose to other infections that may be life-threatening. Thus, averting preventable infections is imperative in GD patients. Summary: The advent of vaccines demonstrated to be safe and efficacious against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has favorably impacted the COVID-19 pandemic epidemiology. However, patients on ISTs were excluded from initial vaccine clinical trials. Thus, only limited and incomplete data are available currently regarding the potential impact of immunosuppression on immune response to or efficacy of the SARS-CoV-2 vaccines. However, new insights are emerging from SARS-CoV-2 vaccine studies, and impacts of ISTs on conventional vaccines are useful to consider. Mechanisms of immunosuppressive agents commonly used in the treatment of GD are reviewed with respect to implications for immune responses induced by SARS-CoV-2 vaccines. ISTs discussed include corticosteroids; alkylating agents; antimetabolites; calcineurin or mammalian target of rapamycin inhibitors; CD38+, CD20+, or CD19+ cell depletion; and complement protein C5 inhibition. Key Messages: Many immunosuppressive therapies may potentially attenuate or impair protective immunity of the SARS-CoV-2 vaccines. However, as vaccines currently in use employ mRNA or nonreplicative viral vectors, they appear to be safe in patients on immunosuppression, further favoring vaccination. Moreover, predominant SARS-CoV-2 vaccines are likely to afford at least partial protective immunity through one or more immune mechanisms even in patients on IST. Guidelines and emerging strategies are also considered to optimize vaccine protection from COVID-19.

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“…Most cases occur in Caucasian patients in the sixth decade of their life, with gender predominance in females (male-to-female ratio 1:1.8). However, specific reports reveal male predominance in some countries such as Greece [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

DNAJB9 Fibrillary Glomerulonephritis With Membranous-Like Pattern: A Case-Based Literature Review

Sabanis,

Liaveri,

Geladari

et al. 2023

Cureus

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Fibrillary glomerulonephritis (FGN) is a rare immune-mediated glomerular disease traditionally characterized by the presence of amyloid-like, randomly aligned, fibrillary deposits in the capillary wall, measuring approximately 20 nm in diameter and composed of polyclonal IgG. FGN is usually a primary disease with no pathognomonic clinical or laboratory findings. More than that, on light microscopic evaluation, it can receive various histological patterns, rendering its diagnosis indistinguishable. However, the identification by immunohistochemistry of a novel biomarker, DNA-J heat-shock protein family member B9 (DNAJB9), has created a new era in FGN diagnosis even in the absence of electron microscopy. Typically, most patients manifest various degrees of renal insufficiency, hypertension, microscopic hematuria, proteinuria, and occasionally frank nephrotic syndrome. The prognosis is usually severe and progression to end-stage kidney disease (ESKD) is the rule, given that no specific treatment is available until now, despite the fact that in small studies rituximab-based therapy seems to alleviate the severity and improve the disease progression. Herein, we report the case of a 63-year-old Caucasian man presenting with uncontrolled hypertension, headache, shortness of breath, and lower limb edema. Diagnostic evaluation revealed mild deterioration of kidney function, nephrotic range proteinuria, and faint IgGκ monoclonal bands in serum and urine immunofixation. After negative meticulous investigation for secondary nephrotic syndrome causes, the patient underwent a kidney biopsy. Biopsy sample showed two glomeruli with mesangial expansion and thickened glomerular basement membrane (GBM) on light microscopy, a pattern masquerading as membranous nephropathy stage III-IV, while IgG and C3 were 1-2+ on GBM and mesangium in immunofluorescence. Thickened GBM with fibrils on electron microscopy were found, while DNAJB9 in immunohistochemistry was positive, confirming FGN. Once diagnosis of FGN was made, a combination of steroids with rituximab was initiated while the patient was receiving the standard anti-hypertensive therapy, simultaneously with a sodium-glucose cotransporter-2 (SGLT2) inhibitor. The 12-month follow-up showed approximately 85% decrease in proteinuria alongside stabilization of kidney function and blood pressure normalization. Hence, in this article, we aim to highlight that DNAJB9-associated FGN may mimic membranous glomerulopathy stage III-IV on light microscopy, especially when a small kidney sample with extensive involvement by fibrils of GBM is examined. Moreover, we underscore the fact that ultramicroscopic examination is of crucial importance in the differential diagnosis of glomerular deposition diseases and that DNAJB9 identification on immunohistochemistry consists of a revolutionary and robust biomarker in FGN diagnosis.

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Clinicopathologic features and treatment outcomes of patients with fibrillary glomerulonephritis

Cited by 6 publications

References 23 publications

Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response

Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response

Immunosuppression in Glomerular Diseases: Implications for SARS-CoV-2 Vaccines and COVID-19

DNAJB9 Fibrillary Glomerulonephritis With Membranous-Like Pattern: A Case-Based Literature Review

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