Fibrillary glomerulonephritis and immunotactoid glomerulopathy
Bela Ivanyi1 and
Peter Degrell2
1 Department of Pathology, University of Szeged and 2 2nd Department of Medicine and Nephrological Center, University of Pécs, Hungary
Correspondence and offprint requests to: Dr Béla Iványi, Department of Pathology, University of Szeged, Állomás u. 2, H-6720 Szeged, Hungary. Email: ivanyi{at}patho.szote.u-szeged.hu
Keywords: amyloid; cryoglobulinaemia; fibrillary glomerulonephritis; immunotactoid glomerulopathy; lupus glomerulonephritis
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Introduction
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Microfibrils or microtubules in the mesangium and the glomerular basement membrane may be observed ultrastructurally in a variety of renal disorders, commonly termed glomerulopathies (GPs) with organized deposits (synonym: glomerular fibrilloses). The microfibrils have no lumen, lack periodicity, are arranged randomly and may be derived from amyloid proteins, immunoglobulins or extracellular matrix proteins. The microtubules have a lumen, tend to be ordered in parallel bundles and are composed of immunoglobulins. The diagnostic algorithm of GPs with organized deposits is shown in Table 1. The pathogenesis and biochemistry of GPs with Congo red-negative organized immunoglobulin deposits have not yet been elucidated fully and their classification remains, therefore, somewhat controversial [1,2]. Some investigators distinguish fibrillary glomerulonephritis (FGN) and immunotactoid glomerulopathy (ITG) on the basis of the substructure of the deposits (fibrillary vs microtubular) and include patients with associated systemic disease [36]. Others regard GPs with Congo red-negative organized immunoglobulin deposits as a single disease with different ultrastructural variants, referring to them as ITG and limiting the diagnosis to patients with primary renal disease [7]. A third group of investigators use the umbrella term fibrillary-immunotactoid glomerulopathy [1,8]. The authors of the present communication share the viewpoint of the first group and survey the features of FGN and ITG separately.
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Table 1. The differential diagnosis of glomerular diseases with organized deposits (based on references 2, 29)
Abbreviations: AL amyloid light chain, AA amyloid associated protein, IH immunohistochemistry, GN glomerulonephritis, GP glomerulopathy
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Fibrillary glomerulonephritis
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A primary GP with Congo red-negative fibrillary deposits was first described by Rosenmann and Eliakim in 1977 [9]. In 1983, Duffy et al. [10] introduced the term fibrillary renal deposits and nephritis, which Alpers et al. [11] shortened to FGN. FGN is characterized by the widespread deposition of randomly arranged, elongated, non-branching microfibrils in the mesangium and glomerular basement membrane (Figure 1), with a focal admixture of finely granular dense unorganized material. In a small percentage of the patients, the deposition of fibrils also involves the tubular basement membranes. The diameters of the fibrils are approximately twice those of the amyloid fibrils and lie in the range 1230 nm, with the majority
20 nm [4,5,913]. At magnifications of less than x40 000, the fibrils have no apparent lumen. Immunofluorescence in most cases reveals polyclonal IgG and C3. The deposits appear in a somewhat smudgy texture in the mesangium and in a confluent granular or pseudolinear pattern along the glomerular basement membrane. The colocalization of IgA, IgM and C1q is observed less frequently. Studies on IgG subtyping with antibodies to IgG1, IgG2, IgG3 and IgG4 have demonstrated that the deposits are either monotypic (predominantly IgG4) or oligotypic (containing both IgG1 and Ig4) [4,6,14]. Light microscopy shows diverse histological patterns: membranoproliferative glomerulonephritis (GN), mesangial proliferative GN, diffuse proliferative GN with endocapillary exudation, sclerosing GN or membranous thickening of the capillary tufts. Crescents may be present and on occasion crescentic FGN is encountered [15,16]. The Congo red and thioflavin T stains are negative.

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Fig. 1. Fibrillary glomerulonephritis. Randomly arranged microfibrillary deposits (diameter: 1823 nm). MES, mesangium.
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The reported incidence of FGN in native renal biopsies of adults lies in the range 0.81.5% [4,6,10,17] and the frequency of the disease is similar to that of anti-glomerular basement membrane nephritis. The peak of occurrence is between the fifth and sixth decades of life and there is an overwhelming predominance in Caucasians [4]. The renal disease is manifested clinically by subnephrotic or nephrotic range proteinuria. The proteinuria is frequently accompanied by gross or microscopic haematuria, hypertension and renal insufficiency. FGN is, in general, a primary renal disease. Rarely, elevated anti-nuclear antibodies, a monoclonal spike in the serum or urine or positive serology for hepatitis C infection are encountered [6]. Tests for cryoglobulins are negative. The course of FGN is usually slowly progressive. Despite the administration of corticosteroids and cytotoxic drugs, end-stage renal disease develops within 24 years in about half of the patients. Fibril deposition recurs in
50% of the transplanted allografts, but the recurrent disease has a relatively benign course [18].
The pathogenesis of fibrillogenesis has not been elucidated. The deposition of fibrils is, in general, limited to the kidney, although there have been occasional reports of extrarenal involvement [17,19,20]. The predominantly renal and glomerular involvement indicates that the specific glomerular environment and the physicochemical properties of the deposited immunoglobulins are the factors that favour fibrillogenesis. The presence of polyclonal IgG suggests an autoimmune process. It is not known why the deposited IgG molecules are subclass-restricted. The compactness and rigidity of subclass-restricted IgG may promote fibril formation. In a series of FGN, the fibrils were shown to colocalize with the amyloid P component, but not fibronectin or fibrillin [21]. In a separate study of a crescentic case of FGN, fibronectin was detected both in the deposits and in a cryoprecipitate that formed after prolonged storage of the patient's serum [15], but it appears that fibronectin is not an essential component of the fibrils.
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Immunotactoid glomerulopathy
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On analogy with the linear crystallization of haemoglobin S, which forms elongated tactoids in the red blood cells during a sickle-cell crisis, the term ITG was applied in 1980 by Schwartz and Lewis [22] to describe the crystalline rod-like particles with an immunoglobulin content deposited in the glomeruli of a patient with the nephrotic syndrome. ITG is characterized by microtubular deposits 1090 nm in outer diameter, with hollow, electron-lucent centres, arranged in parallel arrays in the glomerular basement membrane and in the mesangium (Figure 2) [5,14,23]. In a marked number of cases, the microtubules have an outer diameter of >30 nm and may display a lattice-like pattern. The microtubules may be prominent in the subepithelial space, with intervening basement membrane spikes [2]. Immunofluorescence reveals granular staining for IgG and C3 along the capillary loops and the mesangium. The colocalization of IgA and IgM is rare. The IgG deposits most often have a single light chain (either kappa or lambda). On light microscopy, atypical membranous, membranoproliferative or diffuse proliferative patterns of glomerular involvement are observed, usually without crescents. Stains for amyloid are negative.

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Fig. 2. ITG from a patient with chronic lymphocytic leukaemia. Subendothelial parallel arrays of microtubular deposits (outer diameter: 3540 nm). By immunofluorescence, the deposits showed staining for IgGk. GBM, lamina densa of the glomerular basement membrane; P, podocyte; L, capillary lumen.
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ITG is a very rare disease: in one large series it comprised only 0.06% of all native kidney biopsies [6]. The peak of occurrence is at 60 years of age [5,14]. The clinical presentation is similar to that of FGN, but patients with ITG display a high prevalence of the concurrent or subsequent appearance of monoclonal gammopathy or lymphoproliferative disorders (mainly B-cell lymphocytic leukaemia or small lymphocytic non-Hodgkin's lymphoma) and hypocomplementaemia [6,8,14,24]. Immunoblotting may reveal paraproteinaemia not detected by immunoelectrophoresis alone [14]. Tests for cryoglobulins are negative. ITG can recur in the transplanted kidney [25].
The pathogenesis of formation of microtubules is not known. As in FGN, the deposition of the microtubules is generally limited to the kidney. The abnormal structure of the monoclonal protein, together with its physicochemical properties and tissue affinity, seem to be the key factors governing the crystallization and the unique microtubular appearance. The microtubules sometimes resemble those seen in cryoglobulinaemia. ITG has been reported in association with lymphoproliferative disorders [8], hepatitis C virus infection [26] and leukocytoclastic vasculitis and hypocomplementaemia [27], conditions likewise associated with type II cryoglobulinaemia. Type II cryoglobulins have been detected occasionally in patients initially diagnosed as having ITG [24]. The overlaps in the ultrastructural morphology of the deposits and the underlying diseases have led to the hypothesis that some cases of ITG, and possibly even FGN, may represent a forme fruste of type II cryoglobulinaemia [8,15,26]. Organized monoclonal immunoglobulin deposits with a microtubule diameter smaller than commonly observed in conventional ITG may be present in a few patients with chronic lymphocytic leukaemia or B-cell lymphoma [14].
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Comment
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Some of those who advocate to distinguish FGN and ITG, separate the two conditions on the basis of the size of microfibrils/microtubules (ITG >30 nm; FGN <30 nm) and the arrangement of microfibrils/microtubules (focally parallel in ITG; random in FGN) [3,6]. Unfortunately, this approach by definition excludes cases of ITG with thin microtubules [12,14,28]. The diameter of the microtubules is, therefore, not suggested as a cut-off for the verification of ITG.
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Summary
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The features of GPs with Congo red-negative, non-cryoglobulinaemic deposits have been surveyed. These disorders are rare and clinically heterogeneous and their pathogenesis is unclear. There is controversy concerning the nomenclature of Congo-red negative glomerular fibrilloses. A practical and reproducible approach is to classify these GPs on the basis of the substructure and arrangement of the deposits assessed at conventional electron microscopic magnifications. Accordingly, FGN and ITG can be identified. FGN is characterized by randomly arranged microfibrils (diameter: 1230 nm) composed of subclass-restricted polyclonal IgG and a low incidence of underlying systemic disease. In contrast, ITG is characterized by parallel bundles of microtubules (diameter: 1090 nm) composed mainly of monoclonal IgG and a high incidence of associated lymphoproliferative disease or monoclonal gammopathy. The finding of Congo red-negative organized deposits on renal biopsy should prompt a careful search and follow-up for monoclonal gammopathy, cryoglobulins and haemopoietic malignancy.
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Acknowledgments
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The nephropathological activity of B.I. is supported by OTKA grant T-038271, Budapest, Hungary.
Conflict of interest statement. None declared.
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