Fibrillary and immunotactoid glomerulonephritis

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).

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.