Not all fibrils seen in glomerular disease are amyloid fibrils. Fibrillary glomerulonephritis is a rare glomerular disease that was first described by Rosenmann and Eliakim in a 1977 Nephron article. I am trying hard to get the original article (old Nephron papers are not an easy get). The abstract is available from the article named Nephrotic Syndrome Associated with Amyloid-Like Glomerular Deposits. ” A patient with typical nephrotic syndrome associated with the deposition of an amyloid-like material in the glomeruli is described. The deposits consisted of an electron dense finely granular material which contained immunoglobulins and complement and fibrillar structures which resembled those of amyloid but did not stain with the typical amyloid stains.” It was an amazingly accurate initial description.
It was subsequently recognized as a distinct entity by Duffy 1983. “The study involved 8 patients whose glomeruli contain abundant fibrils in their mesangial matrix and basement membranes. Although the location of these fibrils is very similar to that of amyloid, they are about twice the size of amyloid fibrils, averaging 20 nm in width, and fail to react as amyloid does with special stains. Immunofluorescence microscopic studies are usually positive with antiserums to IgG, often IgM, and in some cases IgA, and also kappa and lambda light chains, C3, and C4. The fibrils are associated with diffuse mesangial widening and increased mesangial matrix strands. Although peripheral glomerular capillary walls appear to be spared initially, their eventual involvement leads to glomerular capillary collapse and glomerular obsolescence. Crescent formation occurred in 5 cases, focally in 3 and diffusely in 2. Tubular basement membrane involvement was seen in 1 case. These patients exhibit hematuria, and proteinuria, and often hypertension and renal insufficiency. Proteinuria was in the nephrotic range in 3 patients in whom involvement of glomerular capillary basement membranes was extensive. Unless electron microscopy is applied to renal biopsies, these cases may be considered to represent mesangiocapillary or rapidly progressive glomerulonephritis, or amyloidosis. The nature of these fibrils is as yet not determined. It is likely that they have been called “atypical amyloidosis” in the past.” Wow, how observant was this report.
The term “fibrillary glomerulonephritis” was coined by Alpers in a 1987 Kidney International article when describing patients with noncongophilic fibrillar glomerular deposits. ” Seven patients were described with renal biopsy findings of mild glomerular abnormalities on light microscopy but with prominent accumulation of randomly-arranged fibrillar material in the mesangium and capillary walls on electron microscopy. This material differed from amyloid in that fibrils were thicker (diameter range 10 to 20 nm) and did not stain with Congo Red. In six of seven cases fluorescence microscopy showed prominent staining for IgG and kappa light chain in mesangium and glomerular capillary walls; in three cases weak lambda chain staining was also present. Stains for IgA, 1gM, and lambda chain were otherwise negative. One biopsy showed equal staining for kappa and lambda light chains, but not for heavy chain components. Clinical findings were heterogeneous. Patients presented with features of nephritis and/or nephrotic syndrome. No patient had an associated lymphoplasmacytic disorder, paraproteinemia, or other evidence of systemic disease. On followup ranging from five months to 12 years, all patients are still alive; six progressed to end stage renal disease requiring dialysis. One patient developed recurrent disease in a renal allograft five years after transplantation. Non-amyloidotic fibrillary glomerulonephritis is an ultrastructurally distinct entity of undetermined etiology. The apparent association with monoclonal lgG and kappa light chain deposition observed in this series deserves further study. In summary, a perplexing picture of non-amyloidotic fibrillary glomerulonephritis with strong tendency to progression to renal failure was described”
A nice early review of the topic was published by Iskander in a 1992 Kidney International article. ” A diagnosis of fibrillary glomerulonephritis was made in 31 renal biopsies from 28 patients on the basis of the electron microscopic identification of glomerular deposits of randomly arranged fibrils that resembled amyloidosis but were larger. This accounted for approximately 1% of all non transplant renal biopsy diagnoses. Renal biopsy specimens with parallel arrays of 30 to 50 nm microtubules (that is, immunotactoid glomerulopathy) were not included in the study. The patients had a mean age of 49 years. The male to female ratio was 1:2 and the ratio of whites to blacks was 8:1, which differs from the 3:1 ratio in our overall biopsy population. All patients had proteinuria (mean 6.0 gm/day), and most had hematuria and renal insufficiency. After a mean follow-up of 24 months, there was 48% renal survival. The light microscopic appearance of the fibrillary glomerulonephritis was quite varied. Capillary wall thickening and matrix expansion were the most frequent alterations. Crescents were noted in 19% of specimens. Morphometric ultrastructural analysis demonstrated a mean fibril diameter of 22 nm. Immunofluorescence microscopy revealed that IgG was the dominant and often the only immunoglobulin class in immune deposits, and subclass analysis revealed that IgG4 was the dominant or exclusive subclass in all specimens tested. It was hypothesized that the relatively homogeneous nature of the immunoglobulin in the immune deposits is the basis for the fibril formation.”
A more recent review of fibrillary GN was authored by Nasr in a 2011 CJASN article. This was a review of 66 patients with fibrillary GN from Mayo Clinic. It remains the largest study ever reported. “The mean age at diagnosis was 53 years. Ninety-five percent of patients were white, and the female: male ratio was almost equal at 1.2:1. Underlying malignancy (most commonly carcinoma), dysproteinemia, or autoimmune disease (most commonly Crohn’s disease, SLE, Graves’ disease, and idiopathic thrombocytopenic purpura), were present in 23%, 17%, and 15% of patients respectively. Presentation included proteinuria (100%), nephrotic syndrome (38%), renal insufficiency (66%), hematuria (52%), and hypertension (71%). The most common histologic pattern was mesangial proliferative/sclerosing GN followed by membranoproliferative GN. During an average of 52 months of follow-up for 61 patients with available data, 13% had complete or partial remission, 43% had persistent renal dysfunction, and 44% progressed to ESRD. The disease recurred in 36% of 14 patients who received a kidney transplant. Independent predictors of ESRD by multivariate analysis were older age, higher creatinine and proteinuria at biopsy, and higher percentage of global glomerulosclerosis. Conclusions from the data included: underlying malignancy, dysproteinemia, or autoimmune diseases are not uncommon in patients with fibrillary GN. Prognosis is poor, although remission may occur in a minority of patients without immunosuppressive therapy. Age, degree of renal impairment at diagnosis, and degree of glomerular scarring are predictors of renal survival”
Nice pictures of the kidney biopsy finding of fibrillary GN was shown by Lusco in a 2015 AJKD publication. It’s part of the AJKD renal pathology atlas. “Fibrillary glomerulonephritis occurs mainly in adults with an average age of around 50 years. It presents with nephrotic syndrome, hematuria, and reduced glomerular filtration rate in about two-thirds of patients. Nearly half of patients progress to end stage kidney disease within 2 to 4 years. Recurrence in allograft kidneys developed in about 1/3 of patients. Light microscopy reveals variable appearance, but commonly with mesangial expansion due to infiltrating extracellular material and frequent lobular membranoproliferative appearance with glomerular basement membrane thickening. Diffuse mesangial or endocapillary proliferation is seen, with crescents present in 15% to 30% of cases (but usually involving a minority of glomeruli in an individual case), and variable glomerulosclerosis. A membranous pattern with spikes is occasionally present. Congo red stain is almost always negative (recent reports have suggested otherwise) Immunofluorescence microscopy reveals mesangial smudgy polyclonal immunoglobulin G (may be IgG4 dominant) and C3, with smudgy, chunky capillary loop staining in proliferative cases, or granular capillary loop staining in membranous pattern cases. Electron microscopy reveals randomly arranged nonbranching fibrillary deposits in the mesangium, and variably in the glomerular capillary basement membrane, corresponding to the immunofluorescence pattern. Usual fibril diameter is 12-22 nm, contrasting with amyloid fibrils which range in thickness from 8-15 nm, but in most cases are between 10-12 nm.” Classic pictures are included.
A monumental advance was the description of DNAJB9 (histochemical) staining in glomeruli by Nasr in a 2018 Kidney International Reports article. “Strong, homogeneous, smudgy DNAJB9 staining of glomerular deposits was seen in all but 2 cases of FGN. The 2 cases that did not stain for DNAJB9 were unique, as they had glomerular staining for IgG only (without k or l) on immunofluorescence. DNAJB9 staining was not observed in cases of amyloidosis, in healthy subjects, or in non-FGN glomerular diseases (with the exception of very focal staining in 1 case of smoking-related glomerulopathy), indicating 98% sensitivity and > 99% specificity. Immunoelectron microscopy showed localization of DNAJB9 to FGN fibrils but not to amyloid fibrils or immunotactoid glomerulopathy microtubules.”
Effective therapy for fibrillary GN remains limited. Almost all of the available papers discuss the use of Rituximab as the preferred treatment. A reasonable review was authored by Hogan in a 2014 Nephrology Dialysis Transplantation article. It was a retrospective chart review involving 12 patients with fibrillary GN who were treated with rituximab (1 gm IV × 2 doses or 375 mg/m2 × 4 doses). Renal function was followed over time. Non-progression of disease was defined as stable/improved serum creatinine with a minimum of 1 year of follow-up. “The median SCr was 2.1 mg/dL, approximate eGFR 40 mL/minute, median proteinuria 4.5497 gm/day at the time of rituximab initiation. Four of 12 patients were non-progressors, 3 of 12 had progressive renal dysfunction without reaching ESRD, and 5 patients reached ESRD. No serious adverse events were noted. B-cell responses to rituximab were not monitored uniformly for all patients, and thus, it was not possible to correlate treatment response and/or relapse with depletion and/or reappearance of B cells.” There was no mention of the response of proteinuria to rituximab therapy.
The most recent review article was written by Rosenstock in a 2019 Kidney International Reports article. “Fibrillary glomerulonephritis is a rare proliferative form of glomerular disease characterized by randomly oriented fibrillar deposits with a mean diameter of 20 nm. By immunofluorescence, the deposits stain for IgG, C3, and k and l light chains, suggesting that the fibrils may be composed of antigen-antibody immune complexes. A recent major advance in the understanding of the pathogenesis of fibrillary GN resulted from the discovery that a major component of the fibrils is DNA-J heat-shock protein family member B9 (DNAJB9), and immunohistochemical staining for DNAJB9 now makes it possible to diagnose fibrillary GN in the absence of ultrastructural evaluation. Fibrillary GN has a poor prognosis, treatment options are currently limited, and transplant recurrence is not uncommon.”
Nephrology Fellowship 