Overview and epidemiology

Fibrillary glomerulonephritis (FGN) was first described in 1977. It is a rare disease, with incidence of less than 1% of native kidney biopsies. It is mostly a disease of Caucasians, with more than 90% of patients in the two largest series self-identified as white. Clinically, the patient with FGN can present with hypertension, proteinuria (full nephrotic syndrome [NS] in up to 50% of patients), hematuria, and renal insufficiency. The mean age of presentation is 55 to 60 years of age.

Diagnosis

Currently, a diagnosis of FGN can only be made via kidney biopsy. On light microscopy, the patterns of injury include mesangioproliferative, membranoproliferative, diffuse proliferative, membranous, diffuse sclerosing, and crescentic forms of glomerulonephritis, although the crescentic variant is only rarely encountered ( Fig. 10.1 A). Congo red staining is negative. On immunofluorescence, immunoglobulin (Ig)G (most cases are polyclonal), kappa and lambda light chains, and complement are present and often have a “smudgy” appearance. On electron microscopy, randomly arranged fibrillary deposits, 16 to 24 nm in diameter (larger than amyloid), are seen in the mesangium and capillary walls ( Fig. 10.1 B).

Fibrillary glomerulonephritis. A, A glomerulus showing infiltration by eosinophilic material, which is expanding mesangial areas and segmentally infiltrating glomerular capillaries. The proliferative pattern in this case is predominantly mesangial. Mesangial areas and glomerular basement membranes typically stain black with a silver stain. In this case, the native matrix has been largely infiltrated and replaced by fibrillary deposits, which are also involving glomerular basement membranes. Jones silver stain, 400x. B, Electron microscopy shows an admixture of fibrils and more granular electron dense deposits. The fibrils are randomly oriented with mean diameter typically ranging from 16-24 nm, typically larger than amyloid fibrils. Electron Microscopy, 68000x.

(Images provided by Leal Herlitz, MD, Department of Pathology, Cleveland Clinic Foundation.)

Etiology

Laser microdissection and mass spectrometry have provided further information on the composition of the classic fibrillary deposits of FGN. This process involves the extraction of glomerular protein, digestion, and identification of the protein constituents via amino acid sequencing. Apoprotein E, serum amyloid P, and Ig heavy/chain C region are some of the identifiable proteins that can help distinguish amyloidosis from FGN from immunotactoid glomerulonephritis (ITGN). The recent discovery of DNAJB9 in the glomeruli of FGN patients by mass spectrometry and use of anti-DNAJB9 antibodies for immunofluorescence/immunohistochemistry will likely transform the diagnosis of this disease and allow for potential therapeutic targets. DNAJB9 is a member of a family of cochaperones to heat shock proteins, which play an important role in the proper folding/unfolding/translocation/degradation of key cellular protein constituents. ^, All these tools are particularly useful since the recent finding of congophilic cases of fibrillary GN. Eighteen of such scenarios were described by the Mayo clinic- this accounted for about 4% of the fibrillary GN cases there.

Most FGN cases at this time are considered idiopathic. In a series of 66 FGN cases from the Mayo Clinic, 15 (23%) were associated with malignancy (mostly carcinomas, including six with multiple myeloma). Ten (15%) were associated with autoimmune disease (Crohn, systemic lupus erythematosus, Graves disease, idiopathic thrombocytopenic purpura, primary biliary cholangitis, ankylosing spondylitis, scleroderma, and Sjögren). Two patients (3%) were hepatitis C positive. A series of 42 FGN patients (26% black) from the University of North Carolina included seven of 26 (27%) testing positive for hepatitis C with no detectable cryoglobulinemia. These patients had the poorest outcome, with all but one proceeding to end-stage renal disease (ESRD). They did not receive antiviral therapy or rituximab. There is one reported case of FGN associated with tuberculosis-related osteomyelitis.

Treatment

Aside from treating an underlying disorder in secondary cases, immunosuppressive (IS) agents including corticosteroids (CS), cyclophosphamide (CYT), mycophenolate, cyclosporine (CyA), azathioprine, and rituximab (RTX) have been used with limited success in the largest series in the literature from the Mayo Clinic. Creatinine at presentation was 2.1 mg/dL, and 29/61 patients were treated with IS: complete/partial renal response (CR/PR) were seen in less than 10%, and at least 40% had “persistent renal dysfunction” or went on to ESRD. In a French series of 27 FGN cases in which 13 received IS, there were six PRs (decrease of proteinuria by at least 50% with stable glomerular filtration rate [GFR]): five with RTX and one with CYT. A case series from Columbia, reporting 12 FGN patients with mean creatinine 2.1 (GFR 39 mL/min) treated with RTX, found only four of 12 had no progression of disease. These nonprogressors had the mildest disease at the time of RTX treatment by clinical parameters (i.e., highest estimated GFR and lowest proteinuria). In an earlier Columbia series of 61 FGN patients, the majority of subjects did not respond to IS (CS, CYT, CyA), although it is noted that the mean presenting creatinine was 3.1 mg/dL. In a series of eight reported crescentic FGN cases treated with CS and CYT, six of eight (75%) patients went on to ESRD. Hence the overall prognosis is guarded at best.

Transplantation

The reported incidence of FGN recurrence in the allograft is varied. In the Mayo series, five of 14 (36%) recurred. In a more recent series from Australia and New Zealand, only one of 13 (8%) patients had recurrence. In an older series of 12 FGN patients who underwent kidney transplantation, reduced allograft and patient survival was observed in those with untreated concomitant monoclonal gammopathy.