Fibrillary glomerulonephritis - difficult diagnosis facilitated by the new diagnostic markers

Fibrillary glomerulonephritis (FGN) is a rare condition, characterized by the glomerular deposition of non-amyloid fibrils. Light microscopy (LM) reveals mesangial expansion with weakly eosinophilic PAS-negative and mainly Congo-negative non-argyrophilic material, or membranoproliferative pattern; and immunofluorescence (IF) demonstrates predominantly polyclonal IgG, С3 and C1q deposits. These findings, suggestive for FGN, can be confirmed by electron microscopy (EM), which shows large (diameter 16-24 nm) nonbranching randomly oriented fibrils in mesangium and along capillary walls [1]. EM was critical to establish FGN diagnosis until 2018, when a new highly specific biomarker of FGN was identified - DNAJB9, a molecule, belonging to a family of proteins that function as “co-chaperones” to heat-shock protein 70. DNAJB9 is localized in the endoplasmic reticulum in all tissues, and it is up-regulated by various inflammatory mediators. Pathogenic role of DNAJB9 in FGN remains unknown, presumably it is related to exaggeration of its physiological role as a stress molecule; anyway, co-localization of DNAJB9 with IgG and complement deposits is characteristic for FGN and not found in amyloidosis or immunotactoid glomerulopathy [1-3]. The cause of FGN is not always established, although up to 50% of patients have a history of malignancies, monoclonal gammopathy, autoimmune diseases, hepatitis C, diabetes mellitus or chronic infections [1, 4]. 52-year-old Caucasian male presented with proteinuria and arterial hypertension. 18 years ago, he underwent inguinal hernioplasty, and same time a perianal fistula was revealed. A year ago, at admission to colorectal clinic, his blood pressure was 150/90 mm Hg, and work-up found proteinuria 1.18 g/L. After fistulectomy he was referred to nephrology, his proteinutia was 2.25 g/L and accompanied by microhaematuria 10-12-20-25 RBC/hpf; his serum creatinine was 135 µmol/L, serum urea 10 mmol/L, uric acid 677 µmol/L; the rest blood chemistry and total blood count were within normal range and infectious screening was negative. ECG, plain chest X-ray, kidney and abdominal ultrasound and ECHO-CG were otherwise normal. He underwent kidney biopsy, LM found 4 totally or partially sclerosed glomeruli, the rest 11 glomeruli were enlarged, with PAS- and Congo-negative amorphous material in mesangium and along capillary walls, without hypercellularity or double-contours; mild diffuse-focal interstitial fibrosis and tubular atrophy; and normal arteries and arterioles. IF showed IgG++, С3+, κ++, λ++ staining co-localized with amorphous material. These findings were suggestive for FGN. Screening for autoimmune diseases was negative, chest and abdominal CT was otherwise normal; bone marrow biopsy did not reveal lymphoma but could not exclude plasma cell dyscrasia, however serum and urine immunochemistry did not confirm monoclonal gammopathy. Review of bone marrow biopsy excluded lymphoproliferative disorder. Review of kidney biopsy confirmed non-immune-complex diffuse glomerulopathy with mesangial and sub-endothelial PAS/Jones/Fuchsin/Congo-negative deposits and with IgG/κ/λ expression ( Figure 1 A-D and Figure 2 A-C). Immunoperoxidase immunohistochemistry with anti-DNAJB9 antibodies showed bright homogenous-granular DNAJB9+++ expression co-localized with PAS-negative glomerular deposits ( Figure 2 D), which confirmed FGN diagnosis. As the detailed work-up did not find neither malignancy, nor monoclonal gammopathy, autoimmune disease, viral hepatitis, nor diabetes mellitus, we concluded, that FGN in this particular case is associated with chronic infection due to persistent for 18 years perianal fistula. Eight months after fistulectomy our patient doing well on nephroprotective treatment only; his blood pressure is within target range, proteinuria 0.3-0.123 g/L, urine sediment is blunt, and serum creatinine 124-102-140 µmol/L. Informed consent was obtained from the individual participant included in the study. None of the authors declares a conflict of interests.

биопсия почки, неамилоидные фибриллы, иммуногистохимия, DNAJB9, kidney biopsy, nonamyloid fibrils, immunohistochemistry, DNAJB9

1. Rosenstock J.L., Markowitz G.S. Fibrillary Glomerulonephritis: An Update. Kidney Int Rep. 2019. 4(7):917-922. doi: 10.1016/j.ekir.2019.04.013

2. Dasari S., Alexander M.P., Vrana J.A. DnaJ heat shock protein family B member 9 is a novel biomarker for fibrillary GN. J Am Soc Nephrol. 2018. 29:51-56, doi: 10.1681/ASN.2017030306

3. Andeen N.K., Yang H.Y., Dai D.F. DnaJ homolog subfamily B member 9 is a putative autoantigen in fibrillary GN. J Am Soc Nephrol. 2018. 29:231-239 doi: 10.1681/ASN.2017050566

4. Andeen N.K., Troxell M.N., Riazy m. et al. Fibrillary Glomerulonephritis. Clinicopathologic features and Atypical Cases from a Multi-Institutional Cohort. CJASN. 2019. 14(12):1741-1750. doi: 10.2215CJN03870319