Introduction

Not all fibrils are created equal when it comes to nephropathy. Fibrillary glomerulonephritis (FGN) and amyloidosis are two of the important but uncommon causes of severe renal dysfunction. But are both usually present clinically as progressive renal failure, commonly associated with nephrotic syndrome?¹ Although they share the common feature of having abnormally deposited protein fibrils in the glomeruli,^2,3 they differ greatly in terms of pathogenesis, histopathological features, and clinical management. Since the treatment methods are different and the prognosis also does, accurate differentiation of these diseases is highly crucial. In light of typical fibril structures, staining characteristics, and clinical implications, this paper has examined the pathological difference between FGN and Amyloidosis.

Overview of Fibrillary Glomerulonephritis (FGN)

FGN is a very rare glomerular disease, composing less than 1% of all renal biopsies.⁴ Large, non-amyloid fibrils deposit within the glomeruli.⁵ The pathogenesis of FGN is not known, but the composition of the fibrils contains immunoglobulins, predominant IgG, with complement proteins such as C3.⁶ Importantly, the FGN fibrils are non-Congophilic and do not take up the Congo red stain, distinguishing them from amyloid fibrils.⁷

Classical presentations of FGN are full-blown nephrotic syndrome with heavy proteinuria, hypoalbuminemia, and edema.⁸ Other features that might be seen include microscopic hematuria and progressive deterioration of renal functions. Many such patients have hypertension.⁹ The course, in many cases, is toward chronic renal dysfunction or even terminal renal failure, but progress is very slow.

FGN is characterized by mesangial expansion and thickening of the capillary walls, usually observed with light microscopy.¹⁰ That might also coincide with other glomerulopathies, such as membranoproliferative glomerulonephritis.¹¹ Immunofluorescence studies reveal the granular deposition of IgG and C3 in the glomeruli.⁴ Electron microscopy would reveal randomly oriented fibrils found in the mesangium and capillary wall.¹² These fibrils are larger and also more randomly oriented compared to those in amyloidosis.

Overview of Amyloidosis

Amyloidosis is a term most often used to describe diseases that are related to the extracellular deposition of insoluble amyloid fibrils into several tissues, including the kidneys.¹³ Renal amyloidosis has two typical varieties: AL, or light-chain amyloidosis, which occurs in the course of plasma cell dyscrasias; and AA, or serum amyloid A-amyloidosis, which accompanies chronic inflammatory diseases.¹⁴ More generally, if there is deposition of misfolded proteins in the form of insoluble fibrils in various tissues, organs can be affected.

Clinically, renal amyloidosis generally manifests as nephrotic syndrome, and patients often advance to end-stage renal failure.¹⁵ In contrast, the symptoms of amyloidosis are nonspecific and involve fatigue and weight loss and, if it is AL Amyloidosis, possibly cardiac amyloidosis secondary to the deposition of amyloids in a broad spectrum of tissues.¹⁶ The prognosis for patients with Amyloidosis depends on the type of amyloid protein but it is poorer for those suffering from AL Amyloidosis than for those with AA Amyloidosis.¹⁷

Amyloid deposits in this condition are Congophilic which means, they positively stain with Congo red and demonstrate characteristic apple-green birefringence under polarized light.¹⁸ Immunofluorescence mostly does not provide any contribution; however, in AL Amyloidosis, light chains may be weakly positive. The ultrastructural features comprise uniform, non-branching fibrils with a diameter measuring 8 to 12nm, much smaller and more orderly than those in FGN.

Key Pathological Differences Between FGN and Amyloidosis

While both FGN and amyloidosis involve fibril deposition in the glomeruli, several important pathological features serve to differentiate these diseases.

Fibril Size and Arrangement

In contrast, FGN shows much larger fibrils with dimensions of 12-24 nm in diameter, which are haphazardly arranged within the mesangium and walls of the capillaries. The amyloidosis demonstrates much smaller fibrils with 8-12 nm size which are straight, non-branching, and more uniform fibrils of amyloid.¹⁹

Congo Red Staining

Congo red staining has been one of the distinguishing tests for FGN from amyloidosis. In the case of FGN, the fibrils cannot take up Congo red because it is referred to as Congo red-negative.⁷ With Amyloidosis, amyloid fibrils can take up Congo red and show apple-green birefringence under polarized light.²⁰ It is one of the very important diagnostic tools that differentiates these two conditions.

Immunofluorescence Pattern

Generally, the immunofluorescence pattern is strong and granular, with IgG and C3 deposits in FGN.⁴ At variance is amyloidosis, which otherwise should generally be negative or weak except for AL amyloidosis, which shall demonstrate faint staining for either kappa or lambda light chains.²¹

Electron Microscopy

These two conditions were further elucidated by electron microscopy. FGN shows fibrils arranged haphazardly, whereas Amyloidosis shows a regular nonbranching fibril.²² Differences in size and organization of the fibrils at electron microscopy become very crucial for diagnostic purposes.

Clinical and Prognostic Implications

Indeed, the clinical separation between FGN and amyloidosis is very important because therapeutic options and prognoses are important criteria in distinguishing between the two.

Treatment Strategies

There is no well-defined treatment for FGN. Management is supportive of the optimization of proteinuria and blood pressure.³ Some of the many immunosuppressive treatments in use for FGN include corticosteroids and rituximab.^23,24 In such cases, the efficacy proves to be variable. On the contrary, treatment depends on the cause. Most of the general chemotherapy regimens that would kill plasma cells in AL Amyloidosis include bortezomib or lenalidomide.²⁵ The treatment for AA Amyloidosis is only supportive because this condition is secondary to the inflammatory disease.²⁶

Prognosis

The prognosis for FGN is usually better than that for AL Amyloidosis, although by this time many patients are terminal for CKD or ESRD.²⁷ As for amyloidosis, the prognosis is rather variable and often worse, due to systemic involvement and possible complications, including that from heart failure.²⁸ Early diagnosis and management are very important in these two conditions. 

Summary

In summary, the common difference between fibrillary glomerulonephritis and amyloidosis is the deposition of fibrils in the glomeruli. On the other hand, pathogenesis, histopathology, and clinical management are very different. Indeed, the most important parameters regarding distinguishing this entity from the pathological standpoint are the size of the fibrils, Congo red staining, immunofluorescence patterns, and electron microscopic findings. Accurate differentiation, whether between FGN and amyloidosis, should be achieved with high timing and accuracy since this would guide appropriate decisions in treatment and thereby help predict the outcome of the patient. These are areas that in the future, more research will have to investigate at a molecular level with interest toward a more specific therapy against both FGN and amyloidosis.