Immunotactoid and Fibrillary Glomerular Diseases—Zebras or Not So Anymore?

Fibrillary glomerulonephritis and immunotactoid glomerulonephritis represent two of the kidney diseases characterized by organized fibrillar deposits. In 1977, the first case of fibrillary glomerulonephritis was described in a patient with nephrotic syndrome whose kidney biopsy showed amyloid-like deposits that did not stain with Congo red (1). The term “fibrillary glomerulonephritis,” however, did not appear in the literature until 1987 (2). Immunotactoid glomerulonephritis was first used to describe the kidney biopsy of a patient with nephrotic syndrome in 1980 (3). For years, whether immunotactoid and fibrillary glomerulonephritis denoted two separate entities or different presentations of a single disease was hotly debated (4, 5). This was due mainly to the fact that they were being differentiated by the size and characteristics of the fibrils. The fibrils in fibrillary glomerulonephritis are solid (as opposed to hollow), randomly arranged, and typically measure 9 to 26 nm in diameter (6−8). In contrast, the fibrils in immunotactoid glomerulonephritis are microtubules with a hollow center ranging from 14 to 90 nm in diameter, typically arranged in parallel patterns (7, 9). Although the distinction seems obvious (Table 1), in practice, accurately measuring the size of the fibrils or identification of the hollow center in the microtubules on electron microscopy is often challenging (10). Moreover, the size overlap of the fibrils/microtubules further adds to the confusion. The debate was finally settled when DnaJ homolog subfamily B member 9 (DNAJB9) was discovered to be involved in the pathogenesis of fibrillary glomerulonephritis but not in immunotactoid glomerulonephritis (11). Now, fibrillary glomerulonephritis is defined by the presence of DNAJB9.

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Histologically, the two entities share many similar features, but there are some subtle differences (Figure 1). On light microscopy, the most common histologic pattern in fibrillary glomerulonephritis is the mesangial proliferative pattern (71%), followed by the membranoproliferative pattern (8, 12). In comparison, endocapillary proliferative (35%) and membranoproliferative (29%) are the most common patterns in immunotactoid glomerulonephritis (9). The membranous pattern and crescents have also been described in both entities. Immunoglobulin (Ig)G is the dominant deposit on immunofluorescence in both fibrillary and immunotactoid glomerulonephritis (6, 8, 9). IgA and IgM can also be found. C1q (in >90%) and C3 (in >60%) are commonly found in both fibrillary and immunotactoid glomerulonephritis. On electron microscopy, the deposits are typically located in the mesangium and the lamina densa of the glomerular basement membranes in fibrillary glomerulonephritis (8). Mesangial deposits also dominate in immunotactoid glomerulonephritis, but infiltration of the lamina densa is limited (9). Tubular basement membrane deposits are rarely seen in fibrillary glomerulonephritis but not in immunotactoid glomerulonephritis.

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Immunotactoid and fibrillary glomerulonephritis characteristics

Citation: Kidney News 13, 4

Fibrillary glomerulonephritis is characterized by expansion of the mesangial matrix with mild hypercellularity (A). The expanded matrix stains periodic acid−Schiff (PAS) positive (B) and silver negative (C). The DNAJB9 immunohistochemical stain is positive in fibrillary glomerulonephritis, with typical extracellular staining, as noted in the glomerulus (D). DNAJB9 may also be noted along tubular basement membranes and peritubular capillaries (E). Unlike as in the amyloid, the deposits are typically Congo red negative (F). Immunofluorescence studies demonstrate smudgy to pseudo-linear staining of glomerular mesangium and capillary walls with IgG (G), and ultrastructural studies show randomly oriented, non-branching fibrils, measuring between 15 nm and 30 nm (H). Amyloid fibrils are typically fine, randomly oriented, non-branching, measuring between 9 and 26 nm in diameter (I).

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Two variants of fibrillary glomerulonephritis have recently been described. First is a congophilic variant of fibrillary glomerulonephritis, which is found in up to 24% in one series (13). It is important to note that in these patients, congophilic deposits are not found outside of the kidney. Proteomics studies by mass spectrometry found that the spectral counts of apolipoprotein E and serum amyloid P component (SAP) were higher in the congophilic fibrillary glomerulonephritis cases, whereas the apolipoprotein A-IV spectral counts were similar to the non-congophilic fibrillary glomerulonephritis. However, none of the spectral counts of the three chaperone proteins in congophilic fibrillary glomerulonephritis were as high as those in amyloid glomerulopathy. More recently, an Ig-negative DNAJB9-positive fibrillary glomerulonephritis was identified (14). So far, the prognosis of Ig-negative DNAJB9-positive fibrillary glomerulonephritis does not appear to be different than IgG-positive DNAJB9-positive fibrillary glomerulonephritis.

Due to their different pathogenesis, it is not surprising that the medical conditions associated with each disease are also different. Fibrillary glomerulonephritis is associated with solid cancers, lymphoproliferative disorders, myeloproliferative disorders, vasculitis, and hepatitis or cirrhosis. Autoimmune diseases, including inflammatory bowel disease, are quite common, whereas monoclonal gammopathy is extremely rare (8, 12). In fact, one study found that only 0.7% of DNAJB9-positive fibrillary glomerulonephritis cases were associated with a monoclonal gammopathy (15). On the other hand, two-thirds of a recent combined series from the Mayo Clinic and Columbia University, involving 73 immunotactoid glomerulonephritis cases, had light-chain restriction demonstrated by immunofluorescence on the kidney biopsy (9). In this series, 82% of the patients with monoclonal deposits and 26% of the patients with polyclonal deposits had a hematologic condition. Lymphoma (53%) was the most common hematologic condition, followed by monoclonal gammopathy of renal significance (MGRS; 22%) and multiple myeloma (8%) in the patients with monoclonal deposits (16). Of the patients with lymphoma, 86% had a chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) clone. The high percentage of CLL/SLL clones has also been reported by others (6). The different etiologies may explain the difference in recurrence rate after kidney transplantation. Recurrence was reported in 21% of DNAJB9-positive fibrillary glomerulonephritis patients who underwent a kidney transplant after a median of 10.2 years (17). In comparison, 60% of patients with immunotactoid glomerulonephritis experienced recurrence within 10 months of kidney transplantation, which is similar to other MGRS-related diseases (9, 18).

So, are fibrillary and immunotactoid glomerulonephritis still considered zebras? It is estimated that there are between 185,000 and 285,000 zebras in the world vs. 58,372,106 horses. Zebras, therefore, represent 0.3%−0.5% of the horse population. Studies estimate that fibrillary glomerulonephritis comprises about 1% of the native kidney biopsies, which is more common than zebras in relationship to horses (7, 12). Immunotactoid glomerulonephritis, on the other hand, makes up only 0.04% of the native kidney biopsies; not only is it a zebra, but it is a Grevy’s zebra, rarest of the zebras (9).