Serum levels of DNAJB9 are elevated in fibrillary glomerulonephritis patients

Abstract

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease. Kidney biopsy is required to establish the diagnosis. Recent studies have identified abundant glomerular deposition of DNAJB9 as a unique histological marker of FGN. We developed an immunoprecipitation-based multiple reaction monitoring method to measure serum levels of DNAJB9. We detected a 4-fold higher abundance of serum DNAJB9 in FGN patients when compared to controls, including patients with other glomerular diseases. Serum DNAJB9 levels were also negatively associated with estimated glomerular filtration rate in patients with FGN. Serum DNAJB9 levels accurately predicted FGN with moderate sensitivity (67%) and with high specificity (98%) and positive and negative predictive value (89% and 95%, respectively). A receiver operating curve analysis demonstrated an AUC of 0.958. These results suggest that serum levels of DNAJB9 could be a valuable marker to predict FGN, with the potential to complement kidney biopsy for the diagnosis of FGN.Kidney International (2019) 95, 1269-1272; https://doi.F ibrillary glomerulonephritis (FGN) is a glomerular disease observed in z1% of native renal biopsies. 1,2 Patients present with proteinuria, hematuria, and impaired renal function. A renal biopsy is required to diagnose FGN. [1][2][3][4] Traditional diagnostic criteria for FGN include the finding, by electron microscopy, of randomly oriented fibrils measuring 10-30 nm in diameter in the mesangium and/or along the glomerular basement membranes. On immunofluorescence, the deposits most commonly stain for IgG, both k and l light chains, and C3. Light microscopy usually reveals mesangial expansion/hypercellularity, with or without duplication of the glomerular basement membranes microscopy. 3 Recently, we 5,6 and others 7 have identified DNAJB9 as a biomarker protein in FGN. Normally, DNAJB9 is localized to endoplasmic reticulum and protects the cells from stress-mediated apoptosis. However, this protein was overly abundant in the extracellular space of FGN glomeruli and absent from glomeruli of healthy controls and a wide variety of non-FGN glomerular diseases (NFGNGDs). 5 Given that FGN is characterized by increased glomerular deposition of DNAJB9, in this study, we measured serum DNAJB9 concentrations in patients with renal disease to assess its potential for distinguishing FGN patients from NFGNGD controls. RESULTSWe wanted to assess whether DNAJB9 has potential as a serum biomarker for FGN. To accomplish this, we developed an immuno-MRM method for measuring serum levels of DNAJB9 in FGN patients and negative controls. FGN patients had significantly higher levels of serum DNAJB9. Multivariate and univariate analyses have suggested that serum DNAJB9 has significant predictive power for FGN. FGN patients have higher serum DNAJB9 levelsFigure 1a 8,9 presents the serum concentrations (expressed in nM) of DNAJB9 in FGN patients and negative controls (normal controls, multiple myeloma patients, NFGNGD patients, and AL patients). FGN patients had significantly hig...

Fibrillary Glomerulonephritis and DnaJ Homolog Subfamily B Member 9 (DNAJB9)

“…58 Serum levels of DNAJB9 was inversely associated with eGFR but this association was not seen in other control groups (except in AL amyloidosis). 58 Therefore, it is possible that both overproduction and decreased excretion of DNAJB9 result in higher serum DNAJB9 levels in FGN patients. 58 Serum DNAJB9 levels can predict the odds of finding FGN.…”

“…Serum levels of DNAJB9 can be measured by immunoprecipitation-linked multiple reaction monitor assay. 58 FGN patients had significantly higher serum levels of DNAJB9 (median serum DNAJB9 1.03 nM) than in normal population (median 0.23 nM), multiple myeloma (median 0.29 nM), NFGNGD (median 0.32 nM) and AL amyloidosis (0.43 nM) patients. 58 Serum levels of DNAJB9 was inversely associated with eGFR but this association was not seen in other control groups (except in AL amyloidosis).…”

“…58 FGN patients had significantly higher serum levels of DNAJB9 (median serum DNAJB9 1.03 nM) than in normal population (median 0.23 nM), multiple myeloma (median 0.29 nM), NFGNGD (median 0.32 nM) and AL amyloidosis (0.43 nM) patients. 58 Serum levels of DNAJB9 was inversely associated with eGFR but this association was not seen in other control groups (except in AL amyloidosis). 58 Therefore, it is possible that both overproduction and decreased excretion of DNAJB9 result in higher serum DNAJB9 levels in FGN patients.…”

Emerging role of clinical mass spectrometry in pathology

“…Through these LMD-MS-based studies, a new variant of FGN termed ‘heavy chain fibrillary glomerulonephritis’ was also identified, which is characterised by Congo red-negative, DNAJB9-negative fibrillar deposits consist of heavy chain immunoglobulins that appear to be distinct from typical FGN both pathogenetically and clinically 72 76 78. More recently, serum levels of DNAJB9 were measured by immunoprecipitation-based MRM and demonstrated to be elevated in patients with FGN when compared with non-FGN glomerular diseases, such as immunoglobulin light chain amyloidosis or multiple myeloma, with adjustment for estimated glomerular filtration rate (eGFR) differences 79. Serum DNAJB9 predicted FGN with a moderate sensitivity (67%) and high specificity (98%) in a discovery cohort 79.…”

“…More recently, serum levels of DNAJB9 were measured by immunoprecipitation-based MRM and demonstrated to be elevated in patients with FGN when compared with non-FGN glomerular diseases, such as immunoglobulin light chain amyloidosis or multiple myeloma, with adjustment for estimated glomerular filtration rate (eGFR) differences 79. Serum DNAJB9 predicted FGN with a moderate sensitivity (67%) and high specificity (98%) in a discovery cohort 79. Further studies are needed to elucidate new variants of FGN, clinical utility of serum DNAJB9 as a non-invasive FGN biomarker, pathogenetic role of DNAJB9 and possibility as a targeted therapy 72.…”