Original ArticlesGlomerular and Tubulointerstitial Diseases

Fibrillary Glomerulonephritis

Clinicopathologic Features and Atypical Cases from a Multi-Institutional Cohort

Nicole K. Andeen, Megan L. Troxell, Maziar Riazy, Rupali S. Avasare, Jessica Lapasia, J. Ashley Jefferson, Shreeram Akilesh, Behzad Najafian, Roberto F. Nicosia, Charles E. Alpers and Kelly D. Smith
CJASN December 2019, 14 (12) 1741-1750; DOI: https://doi.org/10.2215/CJN.03870319

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.

Introduction

Fibrillary GN is diagnosed in 0.5%–1% of native kidney biopsies, and usually presents in middle-aged to older adults with proteinuria, hematuria, and hypertension (1,2). Pathologically, it is characterized by glomerular accumulations of randomly arranged fibrils with a diameter typically larger than amyloid (12–24 nm versus 8–12 nm), positive immunofluorescence microscopy (IF) staining for IgG (usually polytypic) and complement, and negative Congo red staining (1,2), although Congo red-positive fibrillary GN cases have been described (3). No consistent clinical association has been reported for fibrillary GN. Fibrillary GN is more frequently associated with hepatitis C virus (HCV) infection in black people than in white people (4), and up to 30% of patients with fibrillary GN in a French cohort had autoimmune disease (5). Rare cases have been described as paraneoplastic, with remission after cancer treatment (6), or with a neoplasm apparently triggering recurrence of crescentic fibrillary GN in an allograft 14 years post-transplant. Rare familial forms have also been recognized (7,8). The outcome of fibrillary GN is poor with progression to ESKD occurring in 50% of patients within several years of diagnosis (9); the disease may also recur in kidney transplants (1). There are no established therapeutic regimens, although treatment with rituximab has been reported to stabilize disease progression in some patients (5,10–12).

Recent studies have demonstrated that DNAJB9—a heat-shock protein involved in the endoplasmic reticulum stress/unfolded response pathway and which binds aggregation-prone peptides (13–19)—is present in glomerular and extraglomerular immune deposits of patients with fibrillary GN (20–22). DNAJB9 detection in biopsies by immunohistochemistry or mass spectrometry has proven to be reliable for the diagnosis of fibrillary GN. Given the presence of this new diagnostic marker, we sought to reexamine the pathologic features of atypical cases of fibrillary GN and better understand the clinical associations and outcomes of this disease.

Materials and Methods

Kidney pathology biopsy databases from University of Washington (UW), Oregon Health & Science University (OHSU), and Stanford University were searched from 1990 through 2017 for cases of fibrillary GN. Clinical history was obtained through discussion with nephrologists and review of the medical record whenever available. Statistical analyses were performed in Graphpad Prism 7 (San Diego, CA) for univariate analyses and in Stata 13 (College Station, TX) for outcome and multivariable analyses. Descriptive statistics are summarized as median and interquartile range for continuous variables, and were evaluated with Mann–Whitney U tests. The combined primary outcome was ESKD or death. Secondary outcomes were modified from the Kidney Disease Improving Global Outcome guidelines (23), considered for those who did not reach the primary outcome, and were classified as follows: complete remission (<500 mg protein, normal creatinine), partial remission (50% decrease in proteinuria, <2 g/d, no more than 20% increase in creatinine), and persistent CKD (not complete remission, partial remission, or ESKD). Cox proportional hazard regression was used to evaluate the association of potentially relevant covariates with the primary outcome; the final model was verified by examining Cox–Snell residuals. Detailed methods and missing data are provided in Supplemental Materials and Methods.

Results

Pacific Coast Cohort of Patients with Fibrillary GN

The combined data from the biopsy services at our institutions identified 296 kidney biopsies from 266 different patients, summarized in Table 1. Ethnicity data were available in 118 patients: 103 (87%) were white, 9 (7%) were black, 4 (3%) were Hispanic, 1 (0.8%) was Filipino, and 1 (0.8%) was Asian. Compared with white people, black people were more likely to have HCV (seven of nine patients, 78% versus 17%, P=0.0003).

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Table 1.

Clinical characteristics of patients with fibrillary GN at initial diagnosis (n=266)

Pathologic Features of Fibrillary GN

Pathologic findings from 266 patients (296 kidney biopsies) are summarized in Table 2. This large cohort afforded the opportunity to examine subsets of patients with nonclassic clinicopathologic presentations, and the utility of DNAJB9 immunohistochemistry in diagnosing fibrillary GN. DNAJB9 testing was retrospectively performed in 54 (20%) selected cases diagnosed as fibrillary GN or possible fibrillary GN (descriptive diagnoses, with fibrillary GN suggested as possible diagnosis in comment). These cases for DNAJB9 testing were preferentially enriched for those that had atypical features and available tissue (n=29, 11% of total), including Congo red positivity, IgG with monotypic light chain staining by IF, fibril size outside the common range for fibrillary GN, and other clinical or pathologic features which were considered unusual which are detailed by group below. Most, but not all, of the atypical features had raised the possibility of a paraprotein-related kidney disease including amyloid light-chain amyloidosis; patients with monoclonal gammopathy of unknown significance (MGUS) and/or paraprotein-like features on biopsy specimens are detailed in Supplemental Table 1. All cases initially diagnosed as fibrillary GN and 23 of 29 possible fibrillary GN cases (79%) were positive for DNAJB9. The six DNAJB9-negative cases were all immune complex-mediated glomerulonephritides with fibrillar immune deposits that were either monotypic or polytypic and initially diagnosed descriptively, with fibrillary GN suggested as a possible diagnosis in the comment (Supplemental Figure 1, Table 3). After rereview, three remained as descriptive diagnoses, two of these cases were reclassified as probable immunotactoid glomerulopathy, and one case was classified as amyloid light-chain (λ)–type amyloidosis with crescentic GN (Table 1). Diagnostically challenging cases due to morphologically early or advanced features, limited glomeruli for IF, or electron microscopy (EM) (n=25) were also evaluated; DNAJB9 was positive in all of these cases, confirming the diagnosis of fibrillary GN.

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Table 2.

Pathologic characteristics of kidney biopsies with fibrillary GN at initial diagnosis (n=266)

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Table 3.

Cases with descriptive diagnoses and fibrillary GN suggested as a possible diagnosis in comment

Congo Red-Positive Fibrillary GN.

Nine of 181 patients (5%) with available Congo red stains had Congo red-positive deposits in the glomeruli; three also had Congo red-positive deposits in the arterioles. Seven cases were initially diagnosed as fibrillary GN; two cases were diagnosed as atypical amyloid and reclassified as fibrillary GN after DNAJB9 testing (performed in six of nine Congo red-positive cases). Of these nine patients (five men, four women), one had rheumatoid arthritis; one had history of untreated HCV, intravenous drug use, and hypocomplementemia; one had a history of eosinophilic granulomatosis with polyangiitis diagnosed on lung biopsy 11 years prior and had a rising myeloperoxidase-ANCA titer at the time of kidney biopsy; and two patients had a positive proteinase 3 but negative ANCA. One patient with fibrillary GN who was Congo red positive had a circulating paraprotein, which was not significantly different from the percentage of patients with fibrillary GN who were Congo red negative with a paraprotein (11% versus 9%, P=0.56). On biopsy, three of nine cases had crescents (33% versus 20% of Congo red-negative cases, P=0.37). By IF, seven cases had staining for polytypic IgG and two had monotypic IgG-κ–light chain staining. The Congo red-positive cases had a median fibril diameter of 15 nm by EM, but three (33%) had a fibril diameter of 10 nm or smaller by EM, which was a significantly higher proportion than the Congo red-negative cases (33% versus 6%, P=0.02) and a potential confounding factor in distinguishing fibrillary GN from amyloid (Figure 1). There was no significant difference in outcomes between Congo red-positive versus Congo red-negative fibrillary GN cases.

Figure 1.
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.

Small Fibril Diameter.

A total of 15 of 243 patients (6%) had an average fibril diameter measuring 10 nm or less. Four had mesangial-predominant fibril deposition by EM, and three were Congo red positive (described above). Three small-fibril cases also had IgG with monotypic light chain staining by IF, but were Congo red negative. Seven cases had tissue available for further testing, all of which were positive for DNAJB9.

Monoclonality, MGUS, and Light Chain Staining Bias.

A total of 15 patients (6%) had monotypic deposits by IF on frozen tissue, 14 of which (93%) were IgG-κ restricted, and one of which was Congo red positive. Three patients had a history of HCV and three had an underlying neoplasm (one each of myeloproliferative/myelodysplastic disorder, bladder cancer, and hepatocellular carcinoma). Of 20 patients with an MGUS, 19 (95%) had polyclonal fibrillary GN immune deposits, providing evidence against monoclonal gammopathy of renal significance (MGRS) in the great majority of cases. There was no difference between the incidence of monotypic fibrillary GN in patients with an MGUS (5%) and those without an MGUS (4%), substantiating this observation. A single patient (0.4%) had monotypic IgG-κ fibrillary GN, was DNAJB9 positive, and an MGUS, raising the possibility of an MGRS. However, IgG subclass staining, paraffin IF, and information on the type of serum paraprotein were not available to definitively establish this connection, nor was follow-up available with this patient. All seven tested cases with monotypic immune deposits were positive for DNAJB9. Twenty additional patients (8%) had a light-chain staining bias in immune deposits (2+ or greater difference in staining intensity by IF); this was also usually IgG-κ dominant (70%). All four tested cases were positive for DNAJB9. None of the remaining individuals with monotypic deposits or light-chain staining bias developed myeloma or lymphoma during the follow-up period. The presence of monotypic or light chain–restricted immune deposits was not significantly associated with reaching the combined primary outcome.

DNAJB9 Staining of Neoplasms in Patients with Fibrillary GN.

Three patients with fibrillary GN had concurrent neoplasms with available tissue for DNAJB9 testing. Immunohistochemistry for DNAJB9 was negative in a sinonasal melanoma, a urothelial carcinoma, and a hepatocellular carcinoma.

Fibrillary GN and Concurrent Nephropathies.

We rarely observed fibrillary GN in combination with another kidney disease. One man with a history of thyroiditis and no history of malignancy or infections presented with nephrotic syndrome with 18 g of proteinuria on 24 hours urine collection and had concurrent membranous nephropathy and fibrillary GN. This patient showed two populations of glomerular immune deposits (Supplemental Figure 2) as well as extraglomerular deposits. The mesangial and peritubular capillary deposits stained positively for DNAJB9. The subepithelial deposits lacked fibrillar substructure and stained strongly for IgG, but were negative for DNAJB9.

Fibrillary GN in Kidney Allografts.

Eight patients with a primary disease of fibrillary GN who underwent kidney transplant were included (the median follow-up time was 7 years post-transplant): one patient had recurrent fibrillary GN at 3 months, and seven had no evidence of recurrent disease in allograft kidney biopsies. There were two cases of de novo fibrillary GN at 6- and 29-years post-transplant in patients with kidney transplants due to polycystic kidney disease.

Repeat Native Kidney Biopsies in Fibrillary GN.

Nine patients had repeat native kidney biopsies in the setting of worsening eGFR (3) or proteinuria (2), four of whom had been previously treated with immunosuppressives. Two patients with worsening eGFR had developed crescentic fibrillary GN (30% crescents) when original kidney biopsies had lacked crescents. Five (56%) had increased glomerulosclerosis.

Familial Fibrillary GN.

One patient (0.3%) had a mother with a diagnosis of fibrillary GN. She and her mother progressed to ESKD. The patient underwent kidney transplant in 2007, and has had stable allograft function. No other family members are known to have kidney disease.

Clinical Outcome of Fibrillary GN Patients

Follow-up was available in 100 of 266 (38%) patients. The combined primary outcome was defined as ESKD and/or death. At a median time to follow-up or primary outcome of 24 months, 53% reached the primary outcome, 18% had CKD, 18% had partial remission (Table 4), 10% lacked laboratory data to assess kidney function, and one patient (1%) had a spontaneous complete remission without immunosuppressive therapy. After exclusion of six patients with ESKD at diagnosis, on multivariable analyses, male sex (adjusted hazard ratio [aHR] of 3.82 compared with women; 95% confidence interval [95% CI], 1.97 to 7.37) and eGFR at presentation of <45 ml/min per 1.73 m2 (aHR of 8.02 if eGFR was <30 ml/min per 1.73 m2; 95% CI, 1.85 to 34.75; and aHR of 6.44 if eGFR was 30 to <45 ml/min per 1.73 m2; 95% CI, 1.38 to 29.99; when compared with a reference of eGFR >60 ml/min per 1.73 m2) were most strongly associated with the likelihood of reaching the primary outcome (Figure 2, Table 5). Within the cohort examined for survival analysis (n=94, 31 men and 63 women), men had a shorter median time to the primary outcome or follow-up than women (15 versus 32.5 months, P=0.008). There were slight trends for HCV to be more common in men than women (35.5% versus 17.5%, P=0.07) and for men to have a higher eGFR at presentation (34.3 versus 26.8 ml/min per 1.73 m2, P=0.10) in this cohort. There were no significant differences between men and women for any of the other evaluated variables.

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Table 4.

Clinical follow-up of patients with fibrillary GN (n=100)

Figure 2.
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.

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Table 5.

Survival analyses for 94 patients with fibrillary GN without ESKD at diagnosis

The presence of crescents was associated with an increased risk of reaching the combined primary outcome on univariate analysis (hazard ratio, 1.95; P=0.05; Figure 1). Further, of all evaluated variables, the next nearest for consideration for inclusion in the multivariable model was the presence of crescents, with an aHR of 1.78 (95% CI, 0.897 to 3.55; P=0.10) after accounting for the effects of male sex and eGFR (Table 4). Addition of the presence of crescents into the multivariable model had a nonsignificant effect on the model (likelihood ratio test, P=0.18). Notably, a greater proportion of patients with crescents on biopsy specimens received immunosuppression (73%), although this was not statistically significantly different from those without crescents (42%, odds ratio 3.7, P=0.09).

There was no significant difference in outcome for patients who received immunosuppression (n=30) versus those who did not. Of patients who progressed to ESKD, there was no difference in time to outcome between those treated with immunosuppression versus conservative therapy. Most patients treated with immunosuppression received multiple agents. Of the 24 patients treated with steroids, 16 (67%) reached the primary outcome at a median follow-up time of 28 months (interquartile range, 8–38 months). Of the nine patients treated with cyclophosphamide, eight (89%) reached the primary outcome at a median follow-up time of 24 months. Of the eight patients who received rituximab, only one (13%) reached the primary outcome at a median follow-up time of 14 months. Of the remaining seven patients, one had partial remission and six had CKD. Three of the patients who received rituximab also received steroids. Of these agents, only the use of rituximab was significantly associated with lack of progression to ESKD (hazard ratio, 0.435; P=0.008) on follow-up.

Discussion

In this multi-institutional cohort we present the largest biopsy and outcome series of fibrillary GN to date. We present clinicopathologic data for 266 patients with fibrillary GN, including outcome in 100 individuals, and we analyze cases with atypical pathologic features. Novel outcome findings in this study include the identification of male sex and eGFR of <45 ml/min per 1.73 m2 at the time of biopsy as the most important factors predicting progression to ESKD. Using DNAJB9 as a confirmatory stain for cases with unusual features, our series also defines the expanded morphologic spectrum of fibrillary GN.

Our outcome data supports previously published findings of the importance of the degree of kidney impairment at diagnosis (9,24). In contrast with previous investigations, we found that male sex was a significant predictor of progression to ESKD on multivariable analysis. Men comprised 33% of our cohort with survival data—accurately reflecting the female dominance of the overall cohort—and had nonsignificant trends toward higher HCV-positivity rates and a higher eGFR at presentation than women, with no other measured clinical or pathologic differences to account for the difference in outcomes. Large cohort studies of CKD from a variety of etiologies (25–27) and studies of lupus nephritis (28–30) have demonstrated increased risk of progression of kidney disease in men compared with women. In a recent large series, CKD in men progressed more quickly, despite women having a less favorable risk factor profile (31). Some murine models of kidney disease have demonstrated renoprotective effect of estrogens and/or injurious effects of testosterone, but this is not consistent across diseases or strains, precluding uniform conclusions (25,32,33). Proposed mechanisms include sex hormone receptor–mediated effects on glomerular hemodynamics; mesangial, endothelial, and vascular smooth muscle cells; matrix production; interactions with cytokines, growth factors, vasoactive agents, and the renin-angiotensin system; as well as antioxidant effects (25,32).

Similar to previous investigations, approximately 50% of patients with fibrillary GN reached ESKD in 2 years (9,24). In contrast with prior investigations, age, the degree of global glomerulosclerosis, and higher proteinuria at the time of biopsy (24) were NS independent predictors of outcome on multivariable analyses. We did not specifically evaluate the degree of tubular atrophy and interstitial fibrosis for the study, and thus cannot assess the effect of interstitial fibrosis on outcome, which has previously been shown to be an independent predictor of ESKD in fibrillary GN (9).

We did not observe a statistically significant difference in outcome for patients (32%) treated with immunosuppressive therapy, but this analysis may be confounded by the higher incidence of crescents. We suspect crescents play a role in progression to ESKD on an individual basis, and that the measurable effect of crescents may be statistically diminished in our study due to the adjustment for eGFR and the use of immunosuppression. Similar to previous reports (5,11,12), rituximab was significantly associated with nonprogressive CKD in seven of eight patients in this study.

We found a strong association between HCV infection and fibrillary GN in black people, as was previously reported (4), suggesting HCV infection may be an important factor in this population which deserves additional investigation. In one investigation (4), a trend (P=0.06) toward loss of kidney function (defined as doubling of serum creatinine, dialysis, transplant, or death) was observed in patients with HCV; HCV was not a significant predictor of ESKD in our cohort. Of our HCV-positive patients, 72% were diagnosed before the Food and Drug Administration approval of ledipasvir/sofosbuvir in October 2014, potentially influencing the modest rate of treatment. Compared with other cohorts, ours is similarly white predominant (87%); only 1.6% were of Asian background, despite an Asian population ranging from 8% to 31% in our metro areas. There are reports of fibrillary GN in Asian populations (9); the overall incidence has not been reported recently, but was 0.03% in one Chinese cohort (35). The apparently low incidence of fibrillary GN in Asians may be due to differences in genetic or environmental factors, and warrants further investigation.

In this large cohort, fibrillary GN as a possible MGRS represented one of 266 cases (<1%), and we were not able to obtain information to establish this definitively. When combining larger reported series (4,5,9,24), five of 277 patients with fibrillary GN (1.8%) had a reported serum monoclonal protein which matched the monotypic kidney deposits (usually IgG-λ), representing a probable MGRS. However, IgG subclass staining was not reported for these five (24), nor was paraffin IF, which may “unmask” polytypic deposits initially appearing monotypic on frozen IF (35); DNAJB9 was also not available at that time. Monotypic immune deposits in fibrillary GN should prompt additional studies, including IgG subclass analysis, paraffin IF, and DNAJB9 staining, as well as clinical and laboratory evaluation for presence or development of a paraprotein. Our rate of MGUS (7.5%) was only slightly higher than the reported prevalence of MGUS in 60–69 year olds in the general United States population (3% for white people, 6.6% for black people) (36). Monotypic fibrillary GN was seen at a similar rate in patients with and without MGUS (approximately 5%), and 95% of patients with MGUS had polyclonal fibrillary GN, suggesting these diagnoses are more commonly coincident than causal. Taken together, this provides evidence against fibrillary GN as an MGRS in the great majority of cases.

Approximately 5% of fibrillary GN cases had Congo red positivity, suggesting DNAJB9 may share some biophysical properties with amyloid-forming proteins. Monoclonal gammopathy was more prevalent (35%) in Congo red-positive fibrillary GN biopsies in that series (3); in contrast, only one Congo red-positive patient (11%) in our cohort had evidence of a paraprotein, similar to the prevalence of MGUS in Congo red-negative fibrillary GN cases (8%). Because most patients in the Alexander et al. cohort were referred for mass spectrometry for evaluation of amyloidosis, differences in selection and observation bias between our studies may explain the differences in the proportion of MGUS in Congo red-positive fibrillary GN. Thus, small-fibril diameter and Congo red positivity can be seen in fibrillary GN, making the morphologic distinction between fibrillary GN and amyloid challenging in some instances. Immunohistochemical studies for DNAJB9 (or mass spectrometry) are warranted to differentiate fibrillary GN from amyloidosis in these scenarios.

Weaknesses in this study include the retrospective nature and accompanying lack of standardization in treatment regimens. Clinical, laboratory, and follow-up data were gathered from medical records and discussion with clinicians, and was not complete for all patients. Given variability of proteinuria quantification methodologies across practices and institutions, we relied on the presence of nephrotic range proteinuria and cannot completely assess the effect of proteinuria outside of this categoric designation. Reporting biases, incomplete information at time of biopsy, inability to obtain follow-up, and regional practices all influence the findings. However, compared with prior series (36), ours has comparable clinical and pathologic findings, including a similar percentage of patients with MGUS and malignancies. Due to the large multi-institutional sample size, nearly 30-year time period, and tissue availability, it was not feasible to retrospectively obtain studies of potential interest including DNAJB9, paraffin IF, or IgG subclasses on all cases.

This and other studies (20–22) demonstrate the vast majority of cases pathologically diagnosed as fibrillary GN test positive for DNAJB9. We have only observed glomerular DNAJB9 staining in the setting of fibrillary GN; additional use of this biomarker will hopefully advance our understanding of diagnostically challenging cases which share some morphologic features with fibrillary GN. Although no clear benefit for immunosuppressives as a group was noted, rituximab was associated with nonprogression of disease, and further investigation of rituximab’s efficacy is warranted, as is the assessment of whether patients with crescents are more likely to benefit from immunosuppression.

Disclosures

Dr. Najafian reports grants, personal fees, and nonfinancial support from Amicus Therapeutics; other fees from Avrobio; personal fees and other fees from Freeline; grants, personal fees, nonfinancial support, and other fees from Sanofi, outside the submitted work. Dr. Smith reports personal fees from Akcea during the conduct of the study. Dr. Akilesh, Dr. Alpers, Dr. Andeen, Dr. Avasare, Dr. Jefferson, Dr. Lapasia, Dr. Nicosia, Dr. Riazy, and Dr. Troxell have nothing to disclose.

Supplemental Material

This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.03870319/-/DCSupplemental.

Supplemental Materials and Methods.

Supplemental Table 1. Fibrillary GN with pathologic features shared with a paraprotein-related GN or amyloidosis (n=32), and/or in patients with a serum paraprotein (n=22), or an atypical lymphoid infiltrate on kidney biopsy (n=1).

Supplemental Figure 1. Representative electron microscopy images from cases initially diagnosed as possible fibrillary GN, which were negative for DNAJB9, corresponding with cases from Table 3 (1) Case 1, (2) Case 2, (3) Case 3, (4) Case 4, (5) Case 5, (6) Case 6.

Supplemental Figure 2. Coincident fibrillary GN and membranous nephropathy A) Glomerulus with subepithelial “spikes” (Jones silver stain, ×630) and mesangial expansion with segmental endocapillary hypercellularity (PAS stain, ×400).

Acknowledgments

We would like to thank Michael Lasarev, MS, of the OHSU Biostatistics and Design Program (partially supported by UL1TR002369 [OHSU Clinical and Translational Science Awards]) for guidance with the statistical analysis. We also thank the renal pathology laboratory staff at UW, OHSU, and Stanford, and the nephrologists who provided follow-up information.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • Received March 29, 2019.
  • Accepted August 2, 2019.

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Fibrillary Glomerulonephritis
Nicole K. Andeen, Megan L. Troxell, Maziar Riazy, Rupali S. Avasare, Jessica Lapasia, J. Ashley Jefferson, Shreeram Akilesh, Behzad Najafian, Roberto F. Nicosia, Charles E. Alpers, Kelly D. Smith
CJASN Dec 2019, 14 (12) 1741-1750; DOI: 10.2215/CJN.03870319
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