Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response

Abstract

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.

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

“…The identification of DNAJ homolog subfamily B member 9 (DNAJB9), a co-chaperone of the heat-shock protein 70 family members, which was first related to FGN in 2017, now serves as a 98% sensitive and, according to recent studies, 100% specific FGN biomarker. It is found in all biopsy specimens and almost 80% of the suspected cases [ 16 , 17 ]. DNAJB9 is mainly an intracellular protein, normally found in the endoplasmic reticulum of all cellular types.…”

“…Recent research has suggested that rituximab therapy alone or with simultaneous steroid intake offers a non-progression in kidney function in a 12-month observation and a satisfactory reduction in 24-hour proteinuria [ 19 ]. However, no case of complete remission after rituximab therapy was recorded [ 17 ].…”

“…DNAJB9 is mainly an intracellular protein, normally found in the endoplasmic reticulum of all cellular types. The only disease with extracellular presence of DNAJB9 is FGN, where DNAJB9 formates homogenous deposits in the mesangium and the capillary wall of the glomeruli [16][17][18]. The exact role of DNAJB9 in FGN pathogenesis has not been fully determined yet.…”