A Case of Fibrillary Glomerulonephritis With Linear Immunoglobulin G Staining of the Glomerular Capillary Walls.

Crescentic glomerulonephritis is a descriptive term for a type of acute glomerulonephritis (GN). It is not a specific disease but rather a morphologic manifestation of severe glomerular injury that can be caused by a variety of pathogenic mechanisms.[1] The differential diagnosis of crescentic GN includes anti-glomerular basement membrane (anti-GBM) crescentic GN, immune complex crescentic GN, and pauci-immune crescentic GN. In general, anti-GBM GN and pauci-immune GN have a higher frequency and severity of crescent formation.[1]

Fibrillary GN is a glomerular deposition disease that is characterized by extracellular deposition of nonbranching fibrils within the mesangium and capillary walls of renal glomeruli.[1-5] The glomeruli in fibrillary GN most often show diffuse proliferation with increased mesangial cellularity and matrix. Crescents can be found in about 20% of the cases.[4] Fluorescence microscopy of fibrillary GN shows predominantly mesangial IgG and C3 staining with weaker, sometimes granular and irregular, capillary wall staining. The diagnostic feature of fibrillary GN is the presence of randomly arranged fibrils in the mesangium and capillary walls that measure from 15 to 30 nm in thickness.[5]

We report an interesting case of fibrillary GN with extensive crescent formation and linear and pseudolinear immunoglobulin G (IgG) staining of the capillary walls of the glomeruli to illustrate that fibrillary GN should be considered in the differential diagnosis of crescentic GN with linear and pseudolinear IgG deposits within the capillary walls.

REPORT OF A CASE

A 50-year-old man presented with rapidly progressive renal failure of unknown cause. There was a rapid rise in the creatinine levels from 0.8 to 5 mg/dL in 2 months. Twenty-four-hour urinary protein concentration was 2 g. Urine analysis showed proteinuria (2+/4+) and numerous red blood cells but no casts. The initial clinical impression was that of rapidly progressive pauci-immune GN. Laboratory test results were negative for antineutrophil cytoplasmic antibodies and antinuclear antibodies. Tests performed subsequently for circulating anti-GBM antibodies also produced negative results. Serologic test results were negative for human immunodeficiency virus and hepatitis B and C infections.

PATHOLOGIC FINDINGS

The biopsy specimen consisted of renal cortex and outer medulla and contained 17 glomeruli. Two glomeruli were globally sclerosed. Twelve (80%) of the remaining 15 glomeruli showed extracapillary proliferation, giving rise to crescent formation in the glomerular tufts (Figure 1, A and B). The crescent formation was both segmental and circumferehtial. Segmental areas of fibrinoid necrosis with karyorrhexis were also seen in some of the glomeruli. Three glomeruli showed fibrocellular crescents. A few of the glomeruli with crescents showed periglomerular inflammation. The capillaries of glomeruli with cellular crescents were collapsed and showed few or no inflammatory cells. The Bowman

capsule of most affected glomeruli was greatly disrupted or fragmented. On periodic acid--Schiff stain, the glomerular basement membrane of unaffected segments was slightly wrinkled but showed normal appearance and thickness. The Congo red stains revealed no amyloid deposition. Arteries and arterioles were unremarkable; specifically, no vasculitis was observed. Other findings in the biopsy specimen included extensive interstitial nephritis and evidence of acute tubular necrosis. Immunofluorescence examination of 5 glomeruli revealed diffuse linear and pseudolinear deposition of polyclonal IgG (++++/4+) (Figure 2, A), IgA (+/4+), C1q (+/ 4+), and C3 (++/4+) along the glomerular capillary walls. In the mesangial areas, there was nonspecific granular deposition of IgM (+/4+), C1q (+/4+), and C3 (++/4+), but no significant IgG or IgA was appreciated. Fibrin deposition was found in areas of fibrinoid necrosis within the glomeruli (Figure 2, B) and in the interstitium. The interstitium and tubular basement membranes did not reveal immune complex deposition. Electron microscopic examination of one glomerulus revealed distortion and thickening of the glomerular capillary walls by the presence of numerous, 29-nm-thick, nonbranching fibrils arranged within an amorphous matrix. The fibrillary material was located predominantly in the subepithelial areas of the capillary wall (Figure 3), with occasional deposits in the subendothelial areas. These fibrils were also observed in the mesangial areas. No electron dense immune complexes were observed, but there was severe damage to glomerular visceral epithelial cells with diffuse effacement of their foot processes and focal detachment of cells from the basement membrane. The tubules and interstitium and peritubular capillaries did not reveal fibrillary deposits. Based on the findings of light and immunofluorescence microscopy and the presence of the fibrillary deposits on electron microscopy, a diagnosis of fibrillary GN was rendered.

[Figures 1-3 ILLUSTRATION OMITTED]

COMMENT

Fibrillary GN is a glomerular deposition disease that is characterized by infiltration of the glomerular capillary walls and mesangium by fibrillary material. Fibrillary GN accounts for about 1% of all nontransplant renal biopsy specimens. Most patients with fibrillary GN present with nephrotic syndrome, hematuria, and renal insufficiency and develop end stage renal disease within 2 to 4 years of diagnosis.[4,5] The origin of the fibrillary deposits is not known, although an association with lymphoproliferative disorders has been noted.[1]

Light microscopy of fibrillary GN is variable, but glomerular capillary wall thickening, mesangial matrix expansion, and hypercellularity are the common histologic abnormalities.[1] Crescent formation occurs in about 20% of the cases, most of which are fibrous crescents with little activity.[4] Extensive crescent formation and fibrinoid necrosis are uncommon findings in fibrillary GN. Immunofuorescence microscopy reveals staining of predominantly the mesangium and capillary walls for IgG and C3. Iskander et al[5] found that of 31 cases of fibrillary GN, the staining was exclusively mesangial in 1, in 12 it was predominantly mesangial with segmentally variable capillary wall staining, and in 17 it was diffuse and global, involving capillary walls and mesangium. The capillary wall staining was ribbon-and-band-like rather than granular. In 4 of 24 cases, Fogo et al[4] noted a pseudolinear pattern of IgG staining in addition to mesangial staining. It is, however, extremely unusual to find only linear or pseudolinear pattern of IgG staining of the capillary walls in the absence of mesangial staining. The diagnosis of fibrillary GN is established on the basis of electron microscopy that shows deposits of fibrils in a random arrangement, with the size of the fibrils varying in diameter from 15 to 30 nm.[5] The fibrils are usually observed in the mesangium and capillary walls, especially the subepithelial areas of the capillary walls.

We report a case of a 50-year-old man with rapidly progressive renal failure with a rise in creatinine levels from 0.8 to 5 mg/dL in 2 months. Renal biopsy specimen showed a severe crescentic GN, with areas of fibrinoid necrosis in the glomeruli. Immunofluorescence microscopy showed coarse linear and pseudolinear deposition of polyclonal IgG and C3 along the capillary walls without significant mesangial deposits, One of the common causes of crescentic GN is anti-GBM crescentic GN. The glomeruli of anti-GBM crescentic GN are characterized by the presence of fibrinoid necrosis and crescent formation. The immunofluorescence microscopy of anti-GBM crescentic GN is characteristic and shows the presence of diffuse global linear staining of glomerular basement membrane for IgG and is accompanied by linear to granular staining for C3.[1] Based on light and immunofluorescence microscopy, the initial impression in this case was that of an anti-GBM crescentic GN. However, electron microscopy in this case showed the presence of numerous, loosely arranged subepithelial deposits of nonbranching fibrillary material, based on which a diagnosis of fibrillary GN was rendered. In addition, tests performed subsequently for anti-GBM antibodies also produced negative results. The presence of crescents in fibrillary GN is not uncommon. However, this case of fibrillary GN is unusual in that (1) the crescents were active, extensive, and associated with fibrinoid necrosis; (2) there was linear or pseudolinear deposition of IgG along the glomerular capillary walls without significant mesangial deposits; and (3) the fibrillary material was predominantly present in the subepithelial areas with only mild involvement of the mesangium. Finally, although most cases of fibrillary GN present with nephrotic syndrome, our case presented with rapidly progressive renal failure. Although, rapidly progressive renal failure is not the most common clinical presentation, many patients with fibrillary GN present with renal insufficiency at the onset.[1]

We present this case to stress that fibrillary GN can present with crescents and linear or pseudolinear IgG deposition along the capillary walls and should be kept in mind in the differential diagnosis of crescentic GN. Electron microscopy plays a critical role in the differentiation of these entities and illustrates that ultrastructural examination is critical in the differential diagnosis of crescentic GN with linear and pseudolinear IgG deposition.

Sanjeev Sethi is supported in part by the College of American Pathologists Foundation Scholars Award, and Oyedele A. Adeyi is supported by the International Society of Nephrology.

References

[1.] Jennette JC, Olson JL, Schwartz MM, Silva FG. Heptinstall's Pathology of the Kidney. 5th ed. Philadelphia, Pa: Lippincott-Raven; 1998:640-656.

[2.] Pronovost PH, Brady HR, Gunning ME, Espinoza O, Rennke HG. Clinical features, predictors of disease progression and results of renal transplantation in fibrillary/immunotactoid glomerulopathy. Nephrol Dial Transplant. 1996;11:837-842.

[3.] Alpers CE. Immunotactoid (microtubular) glomerulopathy: an entity distinct from fibrillary glomerulonephritis? Am J Kidney Dis. 1992;19:185-191.

[4.] Fogo A, Qureshi N, Horn RG. Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis. 1993;22:367-377.

[5.] Iskandar SS, Falk RJ, Jenette JC. Clinical and pathologic features of fibrillary glomerulonephritis. Kidney Int. 1992;42:1401-1407.

Accepted for publication September 11, 2000.

From the Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, Mass.

Reprints: Helmut G. Rennke, MD, Department of Pathology, Amory 3-094, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 (e-mail: [e-mail]).