Fig. 9.1
(a) Amyloidosis, fibrils. (b, c) Fibrillary glomerulonephritis, fibrils. (a, b, c) Transmission electron microscopy. Uranyl acetate and lead citrate. **AX8500, BX8500. In both conditions (a, b), the fibrils are randomly distributed and non-branching. The only difference is that the diameter of the fibrils in amyloidosis generally ranges from 8 to 12 nm in diameter, whereas in fibrillary glomerulonephritis they typically range from 15 to 25 nm in diameter clearly evident on (c)
Fibrillary Glomerulonephritis (Nephropathy)
Renal
This entity, as previously mentioned, first recognized in 1977 remains of uncertain etiology. Alpers coined the term fibrillary glomerulonephritis 10 years later to refer to this entity. Fibrillary glomerulonephritis is characterized by the deposition of randomly disposed fibrils that are Congo red, thioflavin T and S negative, and are thicker than amyloid fibrils with a diameter generally ranging from 15 to 25 nm [21–24] (Fig. 9.1a–c), thicker than those in amyloidosis (Fig. 9.1c). The fibrils are not only predominantly seen in the mesangium, but also frequently present along peripheral capillary walls. Interestingly, amyloid P protein has been shown to be associated with these fibrils [25].
The morphologic glomerular expressions of this disease are indeed heterogeneous. The earliest light microscopic appearance is the expansion of mesangial areas with replacement of the mesangial matrix by amorphous and eosinophilic material noticeable in the hematoxylin and eosin stains (Fig. 9.2a). Amyloidosis is in the differential diagnosis because of the overlap in the light microscopic appearance (Fig. 9.2b). A small percentage of patients with this condition exhibit crescents, though the percentage of glomeruli with crescents is generally small.
Fig. 9.2
(a) Fibrillary glomerulonephritis, X750; (b) Glomerular amyloidosis, X750. (a) Periodic Acid Schiff (PAS) stain. (b) Hematoxylin and eosin stain, X750. (a) Amorphous material replacing mesangial areas and extending to some peripheral capillary walls (b). By light microscopy, similar material as in (a) (eosinophilic and amorphous—“hyaline”), replacing significant portions of a glomerulus with a somewhat nodular pattern of deposition
The accumulation of these fibrils results in variable mesangial expansion sometimes associated with mesangial nodularity, and the deposition of fibrils along peripheral capillary walls results in recognizable wall thickening, which may bring up diabetic nephropathy as a differential diagnostic consideration. Silver stain may be useful in this situation as it is typically positive in the expanded mesangium in diabetes and weak to negative in cases of fibrillary glomerulonephritis and also in amyloidosis (Fig. 9.3).
Fig. 9.3
Glomerular amyloidosis. Silver methenamine stain, X500. Mesangial matrix is replaced by silver negative material. The normal mesangial argyrophilia due to the mesangial matrix is lost
The largest series of cases with fibrillary glomerulonephritis with the longest follow-up published in 2011 highlighted characteristic clinicopathologic features of this disease and emphasized the importance of careful immunomorphologic evaluation to make this diagnosis accurate [26].
An important diagnosis to rule out is diabetic fibrillosis [27, 28] because of the morphologic ultrastructural similarity of the fibrils in this entity with those of fibrillary glomerulonephritis [12]. However, they lack the typical immunofluorescence staining pattern that is associated with fibrillary glomerulonephritis (and described below). In contrast, in these cases, the staining observed is characteristically associated with diabetic nephropathy (i.e., linear staining for albumin and IgG along peripheral capillary walls in glomeruli).
In some selected cases, light chain monoclonality has been demonstrated, most typically kappa, in fibrillary glomerulonephritis [21, 29]. By immunofluorescence, a ribbon-like pattern is characteristically seen for IgG (IgG4 subclass), C3, kappa, and lambda light chains (Fig. 9.4a, b). However, there are cases with a more “granular” immunofluorescence appearance and because of the distribution along peripheral capillary walls in glomeruli it may be confused with membranous nephropathy [30, 31].
Fig. 9.4
Fibrillary glomerulonephritis. ** (a, b) Direct fluorescence; fluorescein stain for IgG. AX350, BX750. Strong smudgy staining of peripheral capillary walls and mesangium
Fibrillary deposits can also be found in the kidney outside the glomeruli. In a study of 1,266 renal biopsies, nine biopsies from eight patients with fibrillary glomerulonephritis were studied carefully ultrastructurally. Extraglomerular fibrillary deposits were seen in 60 % of the cases [32]. Therefore, a better name for this condition is probably fibrillary nephropathy.
Clinically, the manifestations are nonspecific and these patients typically present with proteinuria, sometimes with full blown nephrotic syndrome. Some of these patients exhibit rapidly progressive renal dysfunction and renal prognosis is poor, although remission may occur [26]. The condition is associated with poor prognosis in term of renal function, and renal deterioration occurs rather rapidly. A small percentage of these cases is associated with an underlying plasma cell dyscrasia [26, 29], but most have no associated systemic disorder.
Extrarenal
Fibrillary glomerulonephritis, as its name implies, is primarily a renal (glomerular) disorder. In contrast to amyloidosis, which is a recognized systemic disorder, it is much less common to find reports of extrarenal fibril deposition in this condition.
A few cases of pulmonary hemorrhage in patients with fibrillary glomerulonephritis and similar fibrillary deposits to those seen in the kidney were found in the lung—along alveolar capillary basement membranes [33, 34], including one case occurring in a patient’s post-renal transplantation [35]. In addition, in a patient with fibrillary glomerulonephritis, typical fibrils were demonstrated in the skin associated with leukocytoclastic vasculitis [33].
An autopsy case reported in the literature described massive fibrillary deposits in the liver and bone marrow of a patient with apparent fibrillary glomerulopathy and a concomitant monoclonal gammopathy [36], and another report showed widespread splenic involvement [37]. The previously mentioned study [32] included a case with an autopsy. During the postmortem examination, fibrillary deposits were documented in the pancreas, spleen, lungs, and liver.
The finding of extrarenal involvement in a significant number of patients with fibrillary glomerulonephritis has clearly demonstrated the systemic nature of this condition. However, since this diagnosis requires ultrastructural evaluation for confirmation, it is very likely that extrarenal manifestations in fibrillary glomerulonephritis are underdiagnosed.
Pathogenesis
The pathogenesis of this disorder has been debated for years. Some early reports considered it in the same spectrum with immunotactoid glomerulopathy as one entity [17, 18, 38, 39]. However, a number of publications and case series have clearly and conclusively documented that these are two different diseases each with unique clinicopathologic features [40–44].
The predominant association of these fibrillary deposits with IgG4 has led to the hypothesis that this subtype of IgG has a unique propensity to form fibrils [22]. At one point, it was suggested that these fibrils were unusual morphologic manifestations of cryoglobulins, but this idea has essentially been abandoned, as no sound support has been found for this hypothesis. What we know is that the distribution of the deposits and their composition are consistent with this entity likely representing an immune complex-mediated process [42], which is supported by the finding of a cryoprecipitate in one of the patients with fibrillary glomerulonephritis containing immunoglobulin–fibronectin complexes consistent with immune complexes [45]. This is also supported by a few cases of lupus nephritis that are associated with fibrillary deposits indistinguishable from those seen in fibrillary glomerulonephritis in one way or another. A case of de novo fibrillary glomerulonephritis has been reported arising in a cadaveric renal allograft of a patient who required transplantation because of end-stage lupus nephritis [46], further suggesting that a fibrillary glomerulonephritis represents part of the spectrum of immune complex-mediated renal diseases.
Fibrillary glomerulonephritis is also seen in a small subset of patients with an underlying neoplastic lymphoplasmacytic disorder which suggests that polymerization of monoclonal light chains into fibrils may occur [14, 29, 47].
Cryoglobulinemic Nephropathy
The recognition of renal disease in patients with cryoglobulinemia dates back to the mid-1950s [50]. However, more recently, this condition has significantly increased in incidence, and its recognition by renal pathologists has also improved considerably. The increase in cryoglobulinemic nephropathy parallels the discovery and spread of hepatitis C in the general population.
These patients typically present with a nephrotic syndrome but may also come to seek medical attention because of hematuria, proteinuria, or nephritic syndrome. Important laboratory clues for the diagnosis of cryoglobulinemia include markedly decreased complement levels, sometimes undetectable (most commonly C4), and a very high rheumatoid factor [50]. Systemic manifestations such as purpura, arthralgias, and vasculitis can be seen. Exacerbations and remissions are common components of this disease process. Only rarely these patients progress to end-stage renal disease.
There are several distinct varieties of cryoglobulins and depending on which is the one involved, the immunomorphologic renal manifestations may vary. Some of these cryoglobulins may be monoclonal, but most are polyclonal. Mixed cryoglobulinemia, type II, monoclonal IgM, and polyclonal IgG subtypes represent the most common types of the spectrum of these diseases [50–54]. By immunofluorescence, monoclonality can be detected in the monoclonal cryoglobulinemic nephropathy. Cryoglobulin deposits are most commonly seen in thrombi, subendothelial, or mesangial areas, but can be seen in other glomerular locations and in extraglomerular renal vasculature.
Currently, the majority of these cases are associated with hepatitis C, but cryoglobulinemia has also been shown to occur associated with fibrillary and immunotactoid nephropathies [55]. The development of cryoglobulinemic nephropathy has been linked in these cases to an antigen-driven rheumatoid factor response to chronic hepatitis C infection. Other diseases that are associated with cryoglobulinemia include systemic lupus erythematosus, any chronic liver diseases, infections, other collagen vascular diseases, and lymphoproliferative disorders. Relatively, few cases remain in the category of “idiopathic” or “essential cryoglobulinemia.”
The ultrastructural characteristics of the cryoglobulinemic deposits are quite variable which makes diagnosis a challenge in a significant number of instances. A recent publication analyzing 47 cases of cryoglobulinemic nephropathy focused on the ultrastructural findings (i.e., substructure of electron dense deposits) [56]. The most typical appearance and the one easiest to recognize is represented by deposits with a microtubular substructure with slightly curved pairs of microtubules or cylinders, in various glomerular locations, including in capillary thrombi and in thrombi in arterioles and small arteries in rare cases (Fig. 9.5). The cylinders are each about 25 nm in diameter, and in cross sections the cylinders appear as a hollow center around which 9–12 spokes project [56–61]. The cryoglobulin deposits associated with monoclonal IgG cryoglobulinemia type I, uncommonly associated with renal disease, have been described as composed of either straight structures forming bundles 80-nm wide, which on cross section appear crosshatched or as tubular structures with a fingerprint-like array [50]. Unfortunately, cryoglobulin deposits may have variable ultrastructural appearances [55], which on occasions may not be characteristic enough for proper identification. Also, deposits with the appearance of immune complexes may be seen in cryoglobulinemic nephropathy [56]. The deposits within thrombi are generally the ones that display the most characteristic findings [56]. These cryoglobulins have not been morphologically altered by cellular processes, and they essentially represent aggregates of pristine microtubular aggregates occluding vessels. Ultrastructural identification of cryoglobulin deposits remains crucial for establishing an unequivocal diagnosis.
Fig. 9.5
Cryoglobulinemic nephropathy. Transmission electron microscopy. Uranyl acetate and citrate X. Paired microtubular structures characteristic of cryoglobulins
The most common microscopic appearance seen in renal biopsies is that of membranoproliferative type I pattern with an exudative component and, in some cases, hyaline thrombi in glomerular capillaries are conspicuous (Fig. 9.6). Monocytes may be detected in glomerular capillaries. Rarely an inflammatory vasculitis is seen in the renal vasculature away from glomeruli [57–61]. How often this vasculitis occurs in cryoglobulinemic nephropathy depends on the series of cases studied [50, 56].
Fig. 9.6
Cryoglobulinemic nephropathy. Hematoxylin and eosin stain, AX750. Hyaline thrombi in capillary spaces, exudative changes, and cellular proliferation with accentuation of the electron microscopy
Extrarenal
One of the most important clues to suspect the presence of circulating cryoglobulins is the finding of intravascular hyaline thrombi. These can be seen in any organ. The challenge is to properly identify them as containing cryoglobulins. The thrombi are eosinophilic in the hematoxylin and eosin stains (hyaline) and amorphous, and do not exhibit the fibrillary substructure which is typical of fibrin thrombi; these fibrin thrombi represent the main differential diagnosis. In renal biopsies, immune complexes can also be seen in the form of hyaline intravascular deposits in glomerular capillaries, most often in lupus nephritis. Clinical information and other light, immunofluorescence, and ultrastructural findings can be used to establish a definitive diagnosis. One complication is the fact that deposits with cryoglobulins can coexist with otherwise typical lupus nephritis.
Immunofluorescence evaluation may detect the presence of polyclonal or monoclonal immunoglobulin components associated with the thrombi, but proper tissue is not procured for immunofluorescence in the great majority of these specimens, as the diagnosis may not be suspected. In renal biopsies, the situation is different as routine immunofluorescence and ultrastructural evaluations are carried out, permitting a much more complete assessment. In some cases, where obtaining the tissue is not too invasive, a repeat biopsy with tissue collected for immunofluorescence and electron microscopy in proper fixatives should be recommended to clarify a differential diagnosis.
One of the fundamental problems associated with this diagnosis is that clinical confirmation with detection of cryoglobulins in the serum is difficult and only possible in a relatively small percentage of these cases. The currently available test for detecting cryoglobulins in the serum appears to be very insensitive to detect all cryoglobulins capable to deposit in organized microtubular structures in various organs where the tissue microenvironment makes their organization into recognizable deposits possible. The different cryoglobulins require variable amounts of time (some are quite slow) to precipitate in order to be detected in the serum, and the test only calls for 4 hours of precipitation [48]. In addition, the serum collected from the patients should be kept cold until tested. Otherwise, cryoglobulins can be missed.
Pathogenesis
The main pathology that is seen results from the aggregation of cryoglobulins in the vasculature leading to varying degrees of vascular luminal compromise, including complete occlusion and associated ischemic complications. In rare cases, even infarcts of the affected organs occur. The disappearance of the thrombi from the vasculature may lead to complete reestablishment of function, and this happens with frequency explaining how the renal dysfunction that may be seen in these patients is cyclical. Reducing the amounts of circulating cryoglobulins represents a key therapeutic maneuver to resolve a clinical crisis.
Immunotactoid Glomerulopathy
This even more unusual (very rare) renal condition is characterized by the finding of organized deposits in the glomeruli composed of hollow or cylindrical, microtubular structures with a diameter ranging from 30 to 90 nm predominantly, or at least focally, in a parallel arrangement or displaying intersectioning bundles. These structures can be found in small aggregates, predominantly in the mesangium, replacing mesangial matrix or may arrange forming quite complex structures. These microtubular aggregates resemble cryoglobulins. They are generally not only thicker but also longer than cryoglobulins. By light microscopy, a mesangial proliferative (mesangiopathic) pattern is the most commonly recognized, but other morphologic expressions have also been documented, including a more proliferative pattern akin to membranoproliferative glomerulonephritis. In some cases, expansion of mesangial matrix predominates and in others the appearance mimics a membranous nephropathy. Crescents may be present. Hyalin thrombi are rarely noted in glomerular capillaries. By immunofluorescence, coarse deposits containing predominantly IgG and C3, either in mesangial or peripheral capillary walls, represent the most common finding and often exhibit light chain restriction but mostly IgGκ. These patients generally present with proteinuria/nephrotic syndrome and/or hematuria [12, 18, 19]. There is an important relationship with underlying lymphoproliferative disorders and, in some cases, Sjögren’s syndrome in patients with this disorder. In the series published by Bridoux et al., 7 of the 14 cases reported had chronic lymphocytic leukemia, small lymphocytic B cell lymphoma, and three patients had monoclonal gammopathies of uncertain significance [44]. In contrast to fibrillary glomerulonephritis, renal function tends to remain rather well preserved with mild renal insufficiency remaining for many years. In the more recent series of cases with immunotactoid glomerulopathy, Nasr et al. reported M serum protein spikes in 10 of 16 cases and in 8 of 15 patients tested in the urine. Hematologic malignancies were confirmed in 6 of the patients (38 %) with 5 exhibiting chronic lymphocytic leukemia, small lymphocytic lymphoma, and myeloma in two additional patients [62].
Even though this disease entity has predominantly been documented in the great majority of the cases in the kidney (not extrarenally), it needs to be addressed because it participates in the differential diagnosis of fibrillary and cryoglobulinemic nephropathies, and there are some important conceptual ideas that need to be considered in this comprehensive chapter of diseases with organized deposits mimicking amyloidosis.
Extrarenal Manifestations
Rare cases of systemic immunotactoid disease have been reported in the literature. Perineural deposits with microtubular aggregates similar to those detected in glomeruli have been demonstrated in one patient with clinical mononeuritis multiplex [44]. A case of leukocytoclastic vasculitis in the skin associated with immunotactoid glomerulopathy has been published; however, it is not clear whether this case is indeed an example of immunotactoid or fibrillary disease [63]. An additional case reported 4 years later clearly documents cutaneous vasculitis in a patient with immunotactoid glomerulopathy [64]. More interesting is the report of immunotactoid keratopathy in a patient with a paraproteinemia which suggests that similar structures to those seen in immunotactoid glomerulopathy can be present in rare patients with corneal disease [65]. The failure to recognize this entity outside of the kidney is very likely due to the absolute need for ultrastructural evaluation for proper diagnosis combined with the decreased use to the point of almost complete disappearance of this diagnostic technique in diagnostic pathology, except in fields such as renal pathology.
Pathogenesis
The strong association with lymphoproliferative disorders led to the hypothesis that this disease occurs as a consequence of a peculiar polymerization of monotypical light chains into microtubular structures. Specific physicochemical characteristics of certain light chains involved may predispose them to polymerize in this unusual fashion.
There has been recent speculation that immunotactoid glomerulopathy may be closely associated with cryoglobulinemic nephropathy with some authors suggesting that these two entities are part of a spectrum [66]. Though detection of circulating cryoglobulins in cases of immunotactoid glomerulopathy has only been sporadic, it is a common practice that the detection of cryoglobulins in the serum has been an immediate exclusion for making a diagnosis of ITG. A similar experience has occurred in patients diagnosed as cryoglobulinemic nephropathy where detection of serum cryoglobulins is only possible in about 30 % of the patients attesting to the fact that current laboratory methods of detection of serum cryoglobulins are rather insensitive. One study demonstrated that a serum cryoprecipitate and glomerular deposits were identical biochemically in one ITG case [67] lending support to this hypothesis.
Laser microdissection and mass spectroscopy-based proteomic analysis have been performed in three ITG cases. The profile detected is consistent with the immunofluorescence findings and showed accumulation of complement factors of the classical and terminal pathways and is similar to that seen in cryoglobulinemic nephropathy. Unexpectedly, the three cases also revealed peptides associated with amyloidosis such as amyloid P-component (SAP), apolipoprotein E, and clusterin [54, 55, 62].
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