Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response

<b><i>Background:</i></b> 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. <b><i>Summary:</i></b> 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. <i>DNAJB9</i> 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. <b><i>Key Messages:</i></b> 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.