Fibrillary Glomerulonephritis: Clinicopathologic Features and Atypical Cases from a Multi-Institutional Cohort

Abstract

Background and objectives: Fibrillary GN has been defined as an immune complex-mediated GN with amyloid-like fibrils larger than amyloid which are IgG positive and Congo red negative. With discovery of DNAJB9 as a highly sensitive and specific marker for fibrillary GN, the specificity of the morphologic criteria for establishing the diagnosis of fibrillary GN has come into question.

Design, setting, participants, & measurements: We sought to (1) determine anatomic characteristics that best define fibrillary GN and (2) identify clinical and pathologic features that predict outcomes.

Results: We retrospectively reviewed kidney biopsies from patients diagnosed with fibrillary GN or suspected fibrillary GN between 1997 and 2017 (n=266, 65% female, median age 61). Approximately 11% of kidney biopsies had one or more unusual feature including monotypic deposits, Congo red positivity, or unusual fibril diameter. Fibrillary GN as a possible monoclonal gammopathy of renal significance represented <1% of cases. Immunostaining for DNAJB9 confirmed fibrillary GN in 100% of cases diagnosed as fibrillary GN and 79% of atypical cases diagnosed as possible fibrillary GN. At a median time of 24 months (interquartile range, 8-46 months) after biopsy (n=100), 53% of patients reached the combined primary outcome of ESKD or death, 18% had CKD, and 18% had partial remission. On multivariable analysis, male sex (adjusted hazard ratio [aHR], 3.82; 95% confidence interval [95% CI], 1.97 to 7.37) and eGFR were the most significant predictors of primary outcome (aHR of 8.02 if eGFR <30 ml/min per 1.73 m² [95% CI, 1.85 to 34.75]; aHR of 6.44 if eGFR 30 to <45 ml/min per 1.73 m² [95% CI, 1.38 to 29.99]). Immunosuppressive therapy with rituximab was significantly associated with stabilization of disease progression.

Conclusions: Detection of DNAJB9 is a useful diagnostic tool for diagnosing atypical forms of fibrillary GN. The outcomes for fibrillary GN are poor and progression to ESKD is influenced predominantly by the degree of kidney insufficiency at the time of diagnosis and male sex. Rituximab may help preserve kidney function for select patients with fibrillary GN.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_11_04_CJN03870319.mp3.

Keywords: Congo red; ESKD; ESRD; Monoclonal Gammopathy of Undetermined Significance; antigen-antibody complex; biopsy; chronic kidney failure; cohort studies; confidence intervals; disease progression; female; glomerular disease; glomerular filtration rate; glomerulonephritis; humans; immune complexes; immunoglobulin G; male; outcomes; paraproteinemias; retrospective studies; rituximab.

Graphical abstract

Figure 1.

Fibrillary GN may be Congo red positive, monotypic, and/or have small fibril diameter, but is distinguished by DNAJB9 positivity. (A) Glomerular mesangial expansion by silver-weak material (Jones stain). (B) Features shared with amyloid including a fibril diameter of 9 nm by electron microscopy (transmission electron microscopy). (C) Congo red positivity in glomeruli (apple-green birefringence under polarized light) and (D) arterioles. (E and F) DNAJB9 immunohistochemical stain is positive in (E) glomeruli and (F) arterioles, supporting the diagnosis of fibrillary GN. Original magnification, ×200 in A; ×4800 in B; ×400 in C; ×200 in D; ×200 in E; ×200 in F.

Figure 2.

In multivariable analysis, eGFR at diagnosis and male sex were the most significant predictors of reaching the combined primary outcome of ESKD or death in fibrillary GN. Curves are shown for (A) eGFR at presentation and (B) male sex (the two evaluated factors with the most significant effect on outcome), as well as (C) presence of crescents on biopsy specimens.