DNA J homolog subfamily B member 9 and other advances in fibrillary glomerulonephritis

Abstract

Purpose of review Fibrillary glomerulonephritis (FGN) involves ∼1% of native kidney biopsies and is characterized by glomerular deposition of fibrils larger than amyloid (12–24 nm diameter) composed of polyclonal immunoglobulin G (IgG). The recent discovery of DNA J homolog subfamily B member 9 (DNAJB9) in FGN glomerular deposits has contributed a specific and sensitive biomarker, informing morphologic classification and pathogenesis. This review will consider contemporary FGN incidence and genetics, pathogenesis, (lack of) paraprotein association, variants, treatment, and transplantation. Recent findings DNAJB9 tissue assays have enabled the identification of morphologic variants and improved classification of fibrillary-like glomerular diseases. Together with paraffin immunofluorescence and IgG subclass studies, these have established that FGN is only rarely monoclonal and these patients usually do not have an monoclonal gammopathy. The discovery of DNAJB9 opens new avenues of investigation into FGN pathogenesis, especially those of the unfolded protein response. Treatment for FGN remains empiric, with some encouraging data on rituximab-based therapy. Transplantation is a good option for patients progressing to end-stage kidney disease. Summary Advances building on the discovery of DNAJB9 in FGN should lead to long-term evolution in targeted treatment and outcome of this glomerular disease.

Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response

“…One theory of FGN pathogenesis proposes that DNA-JB9 -perhaps in an altered or misfolded form -is an autoantigen in FGN, which is then bound by IgG [12,14,76]. This fits with the autoimmune glomerular disease construct in which the autoantigen is present in glomerular immune deposits and is supported by the colocalization of DNAJB9 with IgG and fibrils [9,10,77,78].…”

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

“…Interestingly, despite its recognition as the most specific component of the FGN fibrils, DNAJB9 transcription did not result upregulate in the kidney tissue of FGN cases, thus suggesting that its involvement in FGN development is secondary to the binding of circulating molecules to misfolded IgG rather than a glomerular “onsite” production [ 14 , 15 ]. Nevertheless, the exact FGN etiopathogenesis is still largely unexplored [ 2 , 13 , 16 , 17 ].…”

“…In this setting, fibrillary glomerulopathy (FGN) is a rare primary glomerular disease representing less than 1% of native kidney diagnoses, mainly affecting the adult population with a slight female predominance [ 1 ]. FGN was first described in 1977 but its specific etiology has not been clearly identified, whereas a putative association with autoimmune diseases, non-hematological neoplasia, and HCV infection has increasingly emerged [ 2 ]. From a clinical perspective, FGN patients usually present proteinuria (almost 40% nephrotic) and hematuria; since no specific treatment has been identified, FGN harbors an overall poor prognosis with a progressive evolution to chronic end-stage kidney disease within 2–4 years from diagnosis [ 1 , 3 ].…”

“…Fibrils could be properly identified and characterized by means of electron microscopy (EM) only, but this procedure and the specific diagnostic expertise is not widely diffused and requires prolonged diagnostic turn-around time; moreover, misleading cases with ambiguous fibrils features can occur as well as early-stage cases with no demonstrable fibrils in the small samples assessed on EM. To overcome these diagnostic issues, in 2018, DNA J homolog subfamily B member 9 (DNAJB9), a heat shock protein involved in the unfolded-protein response, was identified as one of the main constitutive proteins of FGN fibrils deposits, and subsequently proposed as an innovative immunohistochemical (IHC) diagnostic marker of FGN, allowing its distinction from other kidney diseases with structured glomerular deposits [ 2 , 7 , 8 ].…”

Novel approaches beyond standard immunofluorescence for kidney biopsies

“…FGN is characterized by infiltration of the glomerular matrix by Congo red-negative fibrils (16-24 nm), usually composed of polytypic IgG [10]. DNAJB9 is a sensitive and specific marker for FGN [11,12].…”