| Abstract|| |
Fibrillary glomerulonephritis (Fib GN) is among the newly recognized primary glomerular diseases. This rare cause of end-stage kidney disease has characteristic electron microscopic findings based upon the deposition of randomly distributed (18-22 nm) microfibrills in the mesangium and less frequently in the capillary basement membrane. The main differential diagnosis at the pathological level is amyloidosis; however, the apple green birefringence Congo red positivity of amyloid deposition is not seen in Fib GN. Clinically, the patient usually presents with proteinuria of nephrotic range, and the sine qua non for the diagnosis of Fib GN is the availability of high-magnification electron micrographs. Here is a case report of Fib GN with special emphasis on electron microscopy study and its role in the diagnosis.
|How to cite this article:|
Kfoury HK. Fibrillary glomerulonephritis: A diagnosis not to be missed'. Saudi J Kidney Dis Transpl 2012;23:1246-50
| Introduction|| |
In 1977, Rosenmann and Eliakim were the first to report a glomerulopathy, characterized by infiltration of glomeruli by "amyloid like" fibrillary deposits containing IgG and C3, which resembled amyloid but did not stain with Congo red.  Since then, similar cases have been subsequently reported by various investigators as non-amyloidotic fibrillary glomerulopathy, amyloid stain negative microfibrillary glomerulopathy, fibrillary nephritis and Congo red negative amyloidosis like glomerulopathy. Alpers et al introduced the term fibrillary glomerulonephritis (Fib GN) in 1987.  Fib GN, a rare cause of progressive renal dysfunction, is morphologically a defined entity, characterized by glomerular accumulation of non-branching, randomly arranged fibrils, ranging in diameter from 10 to 30 nm. These fibrils differ from amyloid deposits by virtue of their larger size and lack of reactivity with Congo red and other reagents that are histochemically reactive with amyloid. This entity is distinctive from immunotactoid glomerulopathy on the basis of substructure of the deposits (fibrillary versus microtubular). The pathological mechanism for the organization of the glomerular deposits as fibrils or microtubules in these entities remains obscure. The light microscopic appearance of Fib GN is extremely variable and can mimic most other forms of glomerular disease, especially in hematoxylin and eosin-stained sections. The distinctive abnormality is the accumulation of amorphous, acidophilic, extracellular material in the mesangium, capillary wall or most often both. This results in capillary wall thickening and mesangial matrix expansion.
Here is a case report of Fib GN with special emphasis on electron microscopy study and its role in the diagnosis.
| Case Report|| |
A 45-year-old man was referred to the nephrology outpatient clinic in February 2009 with the chief complaints of headache and facial puffiness. His examination was remarkable for ankle edema and blood pressure of 144/110 mmHg. The work up revealed urinary protein of 3.6 g/24 h urine and serum creatinine level of 1.9 mg/dL. The complete blood count, liver and serological tests for viral (hepatitis B, C, HIV), for anti-nuclear antibodies (ANA) and for anti-DNA and anti-GBM were negative. His complement levels (C 3, C 4) were within the normal range. Ultrasonography of the abdomen showed the kidneys to be of normal size, but with increased parenchymal echogenicity.
Renal biopsy was performed. The specimen consisted of one core of tan tissue. Approximately 95% was cortex and 5% was medulla. Light microscopy study showed eight glomeruli, one of which was globally sclerosed and one glomerulus was segmentally sclerosed. The preserved glomeruli revealed a prominent mesangial expansion by eosinophilic, Periodic acid-Schiff (PAS) positive, silver negative and Congo red negative material. There was also a mild increase in the mesangial cells [Figure 1]. Multiple scattered PAS-positive hyaline thrombi were present in the glomeruli. Thirty percent of the sample showed tubular atrophy and interstitial fibrosis as evidenced on the trichrome stains. There was mild arterial and hyaline arteriolar sclerosis noted.
|Figure 1: The glomeruli show mesangial expansion by eosinophilic PAS-positive material and thickening of the basement membranes (PAS stain, ×200).|
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For immunofluorescence microscopy study, there were four glomeruli present. Three glomeruli were globally sclerosed. The preserved glomerulus exhibits showed focal mesangial and capillary staining with IgG (2+) and C3 (2+) and IgM (1+). The remaining reactants IgA, C1q, kappa, lambda and albumin were negative. Electron microscopy study revealed extensive although not diffuse fusion of the visceral epithelial cells foot processes with microvillous degeneration of the cytoplasm of the podocytes. The mesangium was expanded with organized deposits identified in the mesangial and paramesangial areas. On higher magnification (×30,000), these organized electron-dense deposits were formed of bundles of non-branching, randomly arranged fibrils measuring 15-20 nm in diameter [Figure 2]. The basement membrane was thickened due to fibrils deposition focally. The endothelial cells showed focal loss of the fenestrations.
|Figure 2: Electron microscopy photomicrograph showing mesangial deposits, composed of randomly arranged fibrils 15– 20 nm in diameter (lead citrate, uranyl acetate x30,000).|
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The overall picture was in favor of fibrillary glomerulonephritis. The patient was started on Rituximab 375 mg/m 2 , Prednisolone 20 mg and an angiotensin receptor blocker (ARB) 150 mg OD. The patient was then followed in the outpatient clinic.
| Discussion|| |
Fib GN is an uncommon condition, and currently approximately 150 cases have been reported in the literature.  The incidence of Fib GN in native kidney biopsy of the adults ranges from 0.8 to 1.5%. The peak incidence is between the ages of 50 and 60 years of life, and there is an overwhelming predominance in Caucasians.  This glomerular deposition disease is characterized by infiltration of the glomerular capillary walls and the mesangium by eosinophilic, PAS positive, silver negative, Congo red negative and thioflavin negative material. There are no specific lesions of the tubules or blood vessels noted, but the interstitial fibrosis and tubular atrophy are commensurate with the degree of glomerular obsolescence. The origin of the fibrillary deposits is not known, although immunofluorescence findings suggest an immunologic origin.  It has been demonstrated by immune-electron microscopy that the fibrils of Fib GN actually contain the immunoglobulin seen by immunofluorescence microscopy. 
The clinical presentation does not distinguish fibrillary glomerulonephritis from other primary cases of proteinuria and nephrotic syndrome. All the patients have proteinuria at the time of presentation, and more than half have nephrotic syndrome. Hypertension, hematuria and renal insufficiency frequently accompany proteinuria. The clinical involvement is limited to the kidney, with rare exceptions, at extra-renal sites, e.g. the pancreas, liver and lungs.  Recently, a new form of Fib GN has been described in association with oxycodone addiction. 
The ultrastructural similarities between Fib GN and amyloidosis suggest that the pathogenesis of the two conditions may be similar. The morphologic and immunologic heterogeneity of the glomerular deposits in the Fib GN may be the result of several mechanisms and precursors, analogous to amyloid fibril formation.
On light microscopy, the glomerular pathology generally reflects the distribution of the deposits. Almost every case shows some degree of mesangial expansion by Congo-red negative, PAS positive material, the amount of which may be variable, with secondary glomerular distortion. Crescent formation has been noted in approximately 20% of the cases.  Immunofluorescence study usually shows intense staining for IgG, while C3 is weakly positive. The electron microscopy study reveals the presence of characteristic, non-branching, randomly arranged microfibrills measuring 15-20 nm in diameter in the mesangial and paramesangial areas, and, to a lesser extent, in the glomerular basement membrane, with, sometimes, a focal admixture of finely granular, dense, unorganized material [Table 1].
According to one study, the prognosis of Fib GN differs according to histology;  the membranous type had the best prognosis, with about 87 months interval until the development of end-stage renal disease, whereas diffuse sclerosis and proliferative glomerulonephritis had worse prognosis, with only seven and 20 months interval, respectively, until endstage renal failure. The membranous type, however, is rare and is found in only four of 61 cases in one of the studies. 
Most patients with Fib GN have persistent and progressive disease that often results in end-stage renal disease in 50% of the cases within 2-4 years.  Fibril deposition recurs in about 50% of the transplanted allografts, but the recurrent disease has a relatively benign course.  No effective therapy has been documented, although patients are often treated with corticosteroids, with or without ACE inhibitors, cyclophosphamide or other immunosuppressive drugs. 
To conclude, Fib GN, a rare condition, the diagnosis of which relies on the characteristic electron microscopic appearance, may be missed if high-power photomicrographs are not taken. The pathologist should always keep this entity in the differential diagnosis of proteinuria and therapy-refractory nephrotic syndrome. Furthermore, because there is no effective treatment of Fib GN, a correct diagnosis is of great importance to avoid overtreatment.
| Acknowledgment|| |
The author would like to acknowledge Dr. Shaesta Naseem Zaidi for helping in the preparation of this manuscript.
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Hala Kassouf Kfoury
Consultant and AssistantProfessor, Department of Pathology (32), King Khalid University Hospital, King Saud University, P. O. Box 2925, Riyadh 11461
Kingdom of Saudi Arabia
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]