Nephrology Dialysis Transplantation 2004 19(9):2166-2170; doi:10.1093/ndt/gfh376
Nephrol Dial Transplant Vol. 19 No. 9 © ERA-EDTA 2004; all rights reserved
Editorial Comment
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 [
3–6]. 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 12–30 nm, with the majority
20 nm [
4,
5,
9–13]. 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: 18–23 nm). MES, mesangium.
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The reported incidence of FGN in native renal biopsies of adults
lies in the range 0.8–1.5% [
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 2–4 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 10–90 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: 35–40 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: 12–30 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: 10–90 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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Introduction
Fibrillary glomerulonephritis