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    Immunotactoid and fibrillary glomerulonephritis characteristics

  • 1.

    Rosenmann E, Eliakim M. Nephrotic syndrome associated with amyloid-like glomerular deposits. Nephron 1977; 18:301308. doi: 10.1159/000180846

  • 2.

    Alpers CE, et al.. Fibrillary glomerulonephritis: An entity with unusual immunofluorescence features. Kidney Int 1987; 31:781789. doi: 10.1038/ki.1987.66

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Schwartz MM, Lewis EJ. The quarterly case: Nephrotic syndrome in a middle-aged man. Ultrastruct Pathol 1980; 1:575582. doi: 10.3109/01913128009140563

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Korbet SM, et al.. The fibrillary glomerulopathies. Am J Kidney Dis 1994; 23:751765. doi: 10.1016/s0272-6386(12)70290-1

  • 5.

    Alpers CE. Fibrillary glomerulonephritis and immunotactoid glomerulopathy: Two entities, not one. Am J Kidney Dis 1993; 22:448451. doi: 10.1016/s0272-6386(12)70151-8

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Bridoux F, et al.. Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features. Kidney Int 2002; 62:17641775. doi: 10.1046/j.1523-1755.2002.00628.x

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Fogo A, et al.. Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis 1993; 22:367377. doi: 10.1016/s0272-6386(12)70138-5

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Nasr SH, et al.. Fibrillary glomerulonephritis: A report of 66 cases from a single institution. Clin J Am Soc Nephrol 2011; 6:775784. doi: 10.2215/CJN.08300910

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Nasr SH, et al.. Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants. Kidney Int 2021; 99:410420. doi: 10.1016/j.kint.2020.07.037

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Alpers CE, Kowalewska J. Fibrillary glomerulonephritis and immunotactoid glomerulopathy. J Am Soc Nephrol 2008; 19:3437. doi: 10.1681/ASN.2007070757

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Nasr SH, et al.. DNAJB9 is a specific immunohistochemical marker for fibrillary glomerulonephritis. Kidney Int Rep 2018; 3:5664. doi: 10.1016/j.ekir.2017.07.017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Rosenstock JL, Markowitz GS. Fibrillary glomerulonephritis: An update. Kidney Int Rep 2019; 4:917922. doi: 10.1016/j.ekir.2019.04.013

  • 13.

    Alexander MP, et al.. Congophilic fibrillary glomerulonephritis: A case series. Am J Kidney Dis 2018; 72:325336. doi: 10.1053/j.ajkd.2018.03.017

  • 14.

    Said SM, et al.. Immunoglobulin-negative DNAJB9-associated fibrillary glomerulonephritis: A report of 9 cases. Am J Kidney Dis 2021; 77:454458. doi: 10.1053/j.ajkd.2020.04.015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Said SM, et al.. DNAJB9-positive monotypic fibrillary glomerulonephritis is not associated with monoclonal gammopathy in the vast majority of patients. Kidney Int 2020; 98:498504. doi: 10.1016/j.kint.2020.02.025

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Leung N, et al.. Monoclonal gammopathy of renal significance: When MGUS is no longer undetermined or insignificant. Blood 2012; 120:42924295. doi: 10.1182/blood-2012-07-445304

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    El Ters M, et al.. Recurrence of DNAJB9-positive fibrillary glomerulonephritis after kidney transplantation: A case series. Am J Kidney Dis 2020; 76:500510. doi: 10.1053/j.ajkd.2020.01.018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Said SM, et al.. Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits is associated with high rate of early recurrence in the allograft. Kidney Int 2018; 94:159169. doi: 10.1016/j.kint.2018.01.028

    • Crossref
    • Search Google Scholar
    • Export Citation

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

  • 1 Nelson Leung is with the Divisions of Nephrology and Hypertension and Hematology at the Mayo Clinic, Rochester, MN. Mariam P. Alexander is with the Department of Anatomic Pathology at the Mayo Clinic, Rochester, MN.
Full access

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.

t1

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.

Figure 1.
Figure 1.

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).

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).

Dr. Leung is on an advisory board for AbbVie and Omeros, with all payments going to Mayo. He has two study grants from Omeros and one from Alnylam. Dr. Alexander has no conflicts of interest.

References

  • 1.

    Rosenmann E, Eliakim M. Nephrotic syndrome associated with amyloid-like glomerular deposits. Nephron 1977; 18:301308. doi: 10.1159/000180846

  • 2.

    Alpers CE, et al.. Fibrillary glomerulonephritis: An entity with unusual immunofluorescence features. Kidney Int 1987; 31:781789. doi: 10.1038/ki.1987.66

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Schwartz MM, Lewis EJ. The quarterly case: Nephrotic syndrome in a middle-aged man. Ultrastruct Pathol 1980; 1:575582. doi: 10.3109/01913128009140563

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Korbet SM, et al.. The fibrillary glomerulopathies. Am J Kidney Dis 1994; 23:751765. doi: 10.1016/s0272-6386(12)70290-1

  • 5.

    Alpers CE. Fibrillary glomerulonephritis and immunotactoid glomerulopathy: Two entities, not one. Am J Kidney Dis 1993; 22:448451. doi: 10.1016/s0272-6386(12)70151-8

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Bridoux F, et al.. Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features. Kidney Int 2002; 62:17641775. doi: 10.1046/j.1523-1755.2002.00628.x

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Fogo A, et al.. Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis 1993; 22:367377. doi: 10.1016/s0272-6386(12)70138-5

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Nasr SH, et al.. Fibrillary glomerulonephritis: A report of 66 cases from a single institution. Clin J Am Soc Nephrol 2011; 6:775784. doi: 10.2215/CJN.08300910

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Nasr SH, et al.. Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants. Kidney Int 2021; 99:410420. doi: 10.1016/j.kint.2020.07.037

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Alpers CE, Kowalewska J. Fibrillary glomerulonephritis and immunotactoid glomerulopathy. J Am Soc Nephrol 2008; 19:3437. doi: 10.1681/ASN.2007070757

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Nasr SH, et al.. DNAJB9 is a specific immunohistochemical marker for fibrillary glomerulonephritis. Kidney Int Rep 2018; 3:5664. doi: 10.1016/j.ekir.2017.07.017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Rosenstock JL, Markowitz GS. Fibrillary glomerulonephritis: An update. Kidney Int Rep 2019; 4:917922. doi: 10.1016/j.ekir.2019.04.013

  • 13.

    Alexander MP, et al.. Congophilic fibrillary glomerulonephritis: A case series. Am J Kidney Dis 2018; 72:325336. doi: 10.1053/j.ajkd.2018.03.017

  • 14.

    Said SM, et al.. Immunoglobulin-negative DNAJB9-associated fibrillary glomerulonephritis: A report of 9 cases. Am J Kidney Dis 2021; 77:454458. doi: 10.1053/j.ajkd.2020.04.015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Said SM, et al.. DNAJB9-positive monotypic fibrillary glomerulonephritis is not associated with monoclonal gammopathy in the vast majority of patients. Kidney Int 2020; 98:498504. doi: 10.1016/j.kint.2020.02.025

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Leung N, et al.. Monoclonal gammopathy of renal significance: When MGUS is no longer undetermined or insignificant. Blood 2012; 120:42924295. doi: 10.1182/blood-2012-07-445304

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    El Ters M, et al.. Recurrence of DNAJB9-positive fibrillary glomerulonephritis after kidney transplantation: A case series. Am J Kidney Dis 2020; 76:500510. doi: 10.1053/j.ajkd.2020.01.018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Said SM, et al.. Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits is associated with high rate of early recurrence in the allograft. Kidney Int 2018; 94:159169. doi: 10.1016/j.kint.2018.01.028

    • Crossref
    • Search Google Scholar
    • Export Citation
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