Table 20.1 Classification of the Fibrillary Glomerulopathies

Amyloid (Congo red–positive)

  AL amyloid

     Primary

     Multiple myeloma

  AA amyloid

     Chronic inflammation

 

     Tumors

  Other types of amyloid

Nonamyloid (Congo red–negative)

  Immunoglobulin-derived fibrils

     Cryoglobulinemia

        Mixed essential cryoglobulinemia

        Multiple myeloma

 

     Monoclonal gammopathies

        “Benign”

        Multiple myeloma

     Light chain deposition disease

     Chronic lymphocytic leukemia

     Systemic lupus erythematosus

     Immunotactoid glomerulopathy

Non–immunoglobulin-derived fibrils

     Nail-patella syndrome

     Collagenofibrotic glomerulopathy

     Diabetes mellitus

     Fibrin

     Fibronectin glomerulopathy

     Others

From Korbet SM, Schwartz MM, Lewis EJ. The fibrillary glomerulopathies. Am J Kidney Dis 1994;23:751.

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Editors: Jennette, J. Charles; Olson, Jean L.; Schwartz, Melvin M.; Silva, Fred G.

Hepinstall's Pathology of the Kidney, 6th Edition

Copyright ©2007 Lippincott Williams & Wilkins

> Table of Contents > Volume Two > 20 - Glomerular Diseases With Organized Deposits

20

Glomerular Diseases With Organized Deposits

Melvin M. Schwartz

Organized glomerular deposits, seen by electron microscopy, are among the most dramatic findings in renal pathology. Most frequently, the deposits are organized into elongated, nonbranching fibrils or larger tubules. They also take the form of short curved microtubules (1), spheres (2), crystals (3), “fingerprints” (4), or fibrils with lateral spines (barbed wire) (5). The deposits are usually extracellular in the mesangium, the basal laminae, and the capillary lumens. Rarely, the glomerular cells contain crystals. The pathologist must distinguish organized deposits from the small and intermediate-sized fibrils that are normal features of the extracellular matrix in the immature and adult kidney (6) and the cytoskeletal microtubules and microfilaments of glomerular cells. Glomerular organized deposits occur in various diseases of known and unknown pathogenesis (Table 20.1), and morphologically identical deposits may occur in different diseases.

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Diagnostic Algorithm for Organized Glomerular Deposits

Determining whether patients with organized glomerular deposits have an underlying disease is a primary concern because a specific diagnosis often has therapeutic and prognostic implications. Although the pathologist working without a complete history and laboratory examination may be tempted to render a descriptive diagnosis based solely on the morphology of the organized deposits, this is inadvisable because despite their striking appearance, the morphology of the deposits is usually not pathognomonic. Also, the renal presentations of diseases with organized glomerular deposits are often similar with proteinuria, the nephrotic syndrome, and variable renal insufficiency, and complete clinical, hematologic, and laboratory studies may be necessary to distinguish among them. Therefore, the composition of the deposits, defined by immunohistologic and histochemical analysis, provides a more clinically useful diagnostic approach than either strictly clinical or morphologic classification. The differential diagnosis of organized glomerular electron-dense deposits may be represented as a diagnostic algorithm based on the Congo red stain and the immunochemical composition of the deposits (Fig. 20.1

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Figure 20.1 Algorithm for the evaluation of a patient with organized glomerular electron-dense deposits. CLL, chronic lymphocytic leukemia; LCDD, light chain deposition disease. (From

Korbet SM, Schwartz MM, Lewis EJ. The fibrillary glomerulopathies. Am J Kidney Dis 1994;23:751.

)

Congo Red–Positive Organized Deposits

Amyloidosis

The Congo red stain dichotomizes organized deposits into those that are Congo red–positive (green birefringence under polarized light with the quality of dichromism) (Fig. 20.2) and –negative, and a positive stain is pathognomonic for amyloid. Amyloidosis is the prototypical disease with organized deposits (Fig. 20.3) (see Chapter 19) that appear as 8- to 10-nm-diameter, nonbranching, extracellular fibrils. The principal amyloid fibril proteins seen in renal disease are AA (derived from serum amyloid A protein [SAA], an acute phase reactant) and AL (derived from immunoglobulin light chains). Because the reaction of amyloid fibrils with Congo red dye is a function of the tertiary structure of the amyloid molecule rather than the nature of its precursor proteins, this reaction, which is shared by all forms of amyloid, is the gold standard for the diagnosis (7). However, the current standard of practice

for the diagnosis of amyloidosis requires identification of the amyloid fibril protein, and the pathologist should use immunohistochemistry including specific antisera to kappa and lambda light chains, SAA, and other precursor proteins (see Chapter 19). The next step in the evaluation of organized glomerular deposits is an immunohistochemical evaluation to separate the diseases into those with and without immunoglobulin molecules or fragments in the deposits.

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Figure 20.2 Congo red–positive stain from a biopsy with AL amyloidosis. There is positive staining in the glomerulus, the interstitium, and an interlobular artery. Amyloid fibrils were seen in the same distribution by electron microscopy. (×85.)

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Figure 20.3 Electron micrographs showing glomerular amyloidosis. A: Mesangial deposits of randomly arranged, 12-nm fibrils. MC-mesangial cell process. (Uranyl acetate and lead citrate, ×70,000.) B: Electron-lucent core in amyloid fibrils (arrows). (Uranyl acetate and lead citrate, ×250,000.) (From

Korbet SM, Schwartz MM, Lewis EJ. The fibrillary glomerulopathies. Am J Kidney Dis 1994;23:751.

)

Congo Red–Negative Immunoglobulin-Derived Organized Deposits

Normal or neoplastic plasma cells or B lymphocytes produce immunoglobulin molecules and fragments that can form organized glomerular deposits when deposited in the kidney as aggregates or immune complexes. Diseases that may have glomerular organized immunoglobulin deposits include cryoglobulinemia (primary and secondary), benign monoclonal gammopathy (monoclonal gammopathy of unknown significance [MGUS]), multiple myeloma, light chain deposition disease. and chronic lymphocytic leukemia (Chapter 19), systemic lupus erythematosus (Chapter 12), and hepatitis C (8). The presence of organized glomerular deposits is not pathognomonic for any of these diseases. In each instance, the diagnosis requires clinicopathologic correlation and adherence to established criteria. Discussion of these diseases will be limited to the ultrastructural appearance of the deposits and differential diagnostic features. This section concludes with an in-depth discussion of immunotactoid glomerulopathy.

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Cryoglobulinemia

type I cryoglobulins are monoclonal immunoglobulins usually seen with hematolymphoid neoplasms. Type II cryoglobulins contain a monoclonal immunoglobulin with antiglobulin activity (rheumatoid factor) against a polyclonal immunoglobulin, and they are seen with infections, autoimmune diseases, chronic liver disease (especially hepatitis C), and various forms of proliferative glomerulonephritis. Type III cryoglobulins, composed of a polyclonal immunoglobulin with antiglobulin activity against a polyclonal immunoglobulin, are seen in systemic lupus erythematosus, infections, and various other conditions (9,10). Although type I and II cryoglobulins have both been associated with hematolymphoid neoplasms, it is important to note that glomerular deposits of a monoclonal immunoglobulin are not synonymous with an underlying malignancy (11,12). Ultrastructural study of cryoprecipitates have shown organization into rods, annuli, filaments, cylindrical and annular bodies, globular condensations, and fingerprintlike periodic condensations, and the morphology varies with the class and quality (1) of the immunoglobulin components. Patients with cryoglobulinemia may have similar organized deposits in the glomeruli, usually in the form of tubules measuring up to 1 micron long and from 20 to 30 nm wide. They may be arranged in pairs, bundles, pseudocrystalline arrays, or randomly, or tightly packed (1,13,14,15,16). The tubules often have a thick wall, a definite electron-lucent core, an ill-defined surface coat, and a substructure seen as globular units in the annuli and striations in the tubules. Organized deposits are most frequently seen in type II cryoglobulinemia (Fig. 20.4), but similar structures have also been described with type I cryoglobulinemia (15,17). Although cryoglobulins composed of polyclonal IgG (type III) or monoclonal IgG and small amounts of IgM (type II) form 6-nm-diameter, randomly arranged filaments in vitro, the renal electron-dense deposits seen in the associated diseases are usually amorphous.

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Figure 20.4 Mixed essential cryoglobulinemia. Subendothelial electron-dense deposit from a patient with hematuria, proteinuria, hypocomplementemia, and 760 µg/mL mixed IgG-IgM cryoglobulin. A: The deposits contain randomly arranged, closely packed tubules seen as annuli in cross section. (Uranyl acetate and lead citrate, ×70,000.) B: The tubules are thick walled, with cross-sectional diameter of 30 nm and an electron-lucent core (arrows). (Uranyl acetate and lead citrate, ×250,000.) (From

Korbet SM, Schwartz MM, Lewis EJ. The fibrillary glomerulopathies. Am J Kidney Dis 1994;23:751.

)

Paraproteinemias

The presence of a serum or urine monoclonal immunoglobulin (paraprotein) is part of the definition of plasma cell dyscrasias and dysproteinemias. The clonal proliferation producing the monoclonal immunoglobulin may be subtle (benign monoclonal gammopathy/MGUS) or there may be local and systemic signs and symptoms related to a neoplasm or its paraprotein product. The renal

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pathology seen with the dysproteinemias includes amyloidosis (AL), myeloma kidney, cryoglobulinemic glomerulonephritis, monoclonal immunoglobulin deposition disease (MIDD) (see Chapter 19), and glomerulopathy with organized immune deposits. In multiple myeloma, the principal pathology is immunoglobulin light chain casts in the tubules, but there are reports of crystals in the renal tubules and tubular epithelium, associated with Fanconi's syndrome (see Chapter 19). Glomerular crystals are rare (18,19). Two thirds of the cases of monoclonal immunoglobulin deposition disease (MIDD) have a monoclonal protein in the serum or urine that may be related to multiple myeloma (20,21), and the remainder have no evidence of a plasma cell dyscrasia. The electron-dense deposits in MIDD are usually punctate and finely granular and are located in the lamina rara interna of the glomerular basal lamina and on the interstitial side of the tubular basal lamina. A few reports (22,23,24,25) describe 10- to 15-nm-diameter, randomly arranged or irregularly clustered microfilaments in the tubular basal lamina and in the characteristic glomerular nodules. The fibril size in these cases of MIDD overlaps that of amyloid fibrils, but the deposits are Congo red–negative. It is possible that the fibrils occasionally seen in MIDD are a secondary phenomenon and do not represent an aggregated or polymerized form of the monoclonal immunoglobulin. Because light chains stimulate the production of matrix proteins by mesangial cells in vivo (26), the fibrils may represent matrix proteins rather than organized immunoglobulin molecules (23,24).

The definition of benign monoclonal gammopathy or monoclonal gammopathy of unknown significance (MGUS) includes a circulating paraprotein and the absence of signs of malignant B-cell neoplasm or multiple myeloma. An associated systemic or renal disease related to the paraprotein should exclude patients from this diagnosis. MGUS is an important clinical diagnosis because of its unpredictable long-term outcome. Approximately one third of the patients with this condition develop multiple myeloma, macroglobulinemia, or B-cell lymphoma after 20 years of follow-up (27). On the other hand, many patients with renal diseases that are associated with plasma cell dyscrasias have a serum or urine paraprotein. These include 30% of patients with monoclonal immunoglobulin deposition disease (28), 64% of patients with primary amyloidosis (29), occasional patients with Waldenström's macroglobulinemia (30), and many patients with types I and II cryoglobulinemia (9,10). All these patients could be classified as MGUS, but I consider the glomerular deposits, with or without organization, as complications of the underlying diseases. This allows the clinician to treat the patients with disease-specific therapy. When patients with MGUS and Congo red–negative glomerular immunoglobulin deposits are studied by electron microscopy (31,3233,34,35,36,37,38,39), 13- to 25-nm-diameter microfilaments or 19- to 51-nm-diameter microtubules are described in subepithelial, subendothelial, and luminal deposits. When such cases are reported as fibrillary glomerulonephritis or immunotactoid glomerulopathy (see below, Immunotactoid Glomerulopathy), it should come as no surprise that some of them develop a long-term complication of MGUS. Bridoux et al (36) reported on a patient (no. 6) in whom AL amyloidosis (λ type) developed 3 years after the diagnosis of immunotactoid glomerulopathy and an IgGλ monoclonal gammopathy.

In patients found by screening of serum and urine for monoclonal immunoglobulins using immunoelectropheresis or the more sensitive immunoblotting technique, renal diseases unrelated to the monoclonal protein are found in 46% of the cases (36,40). In my experience, biopsies performed for isolated monoclonal immunoglobulins in the absence of renal functional abnormalities often show no or nonspecific glomerular pathology.

 

Patients with chronic lymphocytic leukemia/lymphoma and other lymphoproliferative disorders may have an associated cryoglobulinemia or paraproteinemia, and some develop glomerulonephritis and the nephrotic syndrome (see Chapter 19). The glomeruli may contain electron-dense deposits, organized as microfibrils or microtubules ranging from 10 to 48 nm in diameter. They are either randomly distributed or focally packed in parallel arrays (Fig. 20.5) (41,42,43,44,45,,47,48). In most instances, the microfibrils/microtubules have an electron-lucent core. Organized deposits in patients with cryoglobulins or a paraprotein are an indication for a hematologic evaluation because neither the organized glomerular deposits nor the serum protein abnormalities are diagnostic of an underlying hematologic neoplasm. This is a critical diagnostic point with therapeutic implications because treatment with remission of the malignancy is frequently associated with resolution of proteinuria and improvement of renal function (36,43).

 

Systemic lupus erythematosus49). Electron-dense deposits, corresponding to immune aggregates seen by immunofluorescence microscopy, are usually amorphous, but in some cases, there are vague small, short, curved microtubules that fail to resolve into definite structures at high magnification. Occasionally, organized deposits occur in subepithelial, subendothelial, transmembranous, and mesangial locations, and similar deposits occur in extraglomerular sites including

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the interstitium, the tubular basement membrane, the peritubular capillary basement membrane, and in the juxtaglomerular apparatus (50). “Fingerprints” are the most characteristic and frequent form of organized deposits, consisting of two to six regularly stacked curved or straight electron-dense bands, 8 to 15 nm in diameter with a center-to-center distance of 19 to 29 nm (Fig. 20.6A) (4514). There are reports of similar deposits in cryoglobulins consisting of polyclonal IgG with traces of IgM (1). Even more rarely, there are distinct tubules or fibrils in association with the fingerprints or in isolation. The tubules have an electron-lucent core and measure 25 to 40 nm in diameter with variable length (5253) (Fig. 20.6B), and the fibrils measure 8 to 27 nm. Hvala et al (50) found organized glomerular deposits in 37 of 185 biopsies (20%) from patients with SLE: The deposits were organized as fingerprints in 32 biopsies (86%), 20- to 100-nm tubules in 3 biopsies (8%), and 18-nm fibrils in 2 biopsies (5%). The fingerprint form of the deposits is quite specific for SLE. In 626 kidney biopsies from patients with primary renal and systemic diseases other than SLE, there were no fingerprint deposits. Finally, organized extracellular deposits are different from the intracellular tubuloreticular structures that are often present within dilated cisterna of the endoplasmic reticulum of glomerular endothelial cells in SLE.

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Figure 20.5 Lymphoproliferative disorder with lymphocytosis, hypocomplementemia, cryoglobulinemia and rapidly progressive glomerulonephritis. Subendothelial electron-dense deposits composed of randomly arranged short tubules, with an electron-lucent core in cross section. GEC, glomerular epithelial cell. ENDO, endothelial cell. (Uranyl acetate and lead citrate, ×25,000.)

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Figure 20.6 Systemic lupus erythematosus. A: “Fingerprint” electron-dense deposit in the perivascular interstitium, composed of five parallel, sharply curved lines with lateral projections. There were similar structures throughout the glomeruli, which showed diffuse glomerulonephritis. EC, endothelial cell. (Uranyl acetate and lead citrate, ×25,000.) B:

Immunotactoid Glomerulopathy (Fibrillary Glomerulonephritis)

There are established clinicopathologic and serologic criteria to diagnosis systemic diseases and hematologic neoplasms with glomerular involvement, and in the presence of organized glomerular deposits, chronic lymphocytic leukemia/lymphoma, lymphoproliferative disorders, SLE, and cryoglobulinemia are appropriate diagnoses. Regardless of the morphology of the deposits, these diagnoses are preferred over a diagnosis that focuses on the appearance of the deposits because the diseases have specific prognostic and therapeutic implications, and so far, the ultrastructural character of the electron-dense deposits does not add diagnostic specificity, prognostic information, or therapeutic guidance to the pathology of these diseases. By exclusion, there remains a group of patients with Congo red–negative, organized glomerular immunoglobulin deposits with no associated systemic disease.

Rosenmann and Eliakim (54) were the first to report glomerular Congo red–negative, “amyloidlike” fibrillary deposits that contained IgG and C3. Similar cases have been reported as nonamyloidotic fibrillary glomerulopathy (55,56), fibrillary nephritis (6), Congo red–negative amyloidosislike glomerulopathy (57), amyloid stain–negative microfibrillary glomerulopathy (58), and Congo red–negative idiopathic fibrillary glomerulopathy (without detectable cryoglobulins or monoclonal gammopathy) (59). These diagnoses take their descriptive names from the ultrastructure of the deposits that are similar in their morphology and random organization to amyloid fibrils and from the negative Congo red reaction. Other cases have been reported as fibrillary glomerulonephritis (FGN) (37,60,62,63). However, this diagnosis confuses the lesion specified by the presence of organized immunoglobulin deposits with the general category of fibrillary glomerulopathies (6,64,65) and the β-fibrilloses (7), diseases with biochemically diverse organized deposits (66). Most of these names are long and cumbersome, and none specifies the immunoglobulin content of the fibrils.

In 1980, Schwartz and Lewis () reported the clinical and pathologic findings of a 49-year-old man who had an 11-year history of proteinuria and the nephrotic syndrome. His renal biopsy was Congo red– and thioflavin T–negative, and the glomeruli contained immunoglobulin and complement (C3) deposits. By electron microscopy, the deposits comprised thick-walled tubules, measuring 35 nm in diameter, organized in parallel arrays. Despite repeated evaluation over a 17-year course of nephrotic syndrome and progressive renal insufficiency that terminated in end-stage renal disease, the patient never developed any of the diseases that previously had been associated with organized immunoglobulin deposits. By analogy to the linear crystallization of hemoglobin S that forms elongated tactoids in red blood cells during sickle cell crisis, the term immunotactoid glomerulopathy (ITG) was coined to emphasize the morphology and the composition of the glomerular deposits.

Korbet et al (68) proposed that biopsies showing either of the ultrastructural forms of the organized immunoglobulin deposits should be included under the single diagnostic rubric of ITG, when patients with diseases associated with organized glomerular immune deposits were excluded from the analysis. It was the author's intention that the diagnosis of ITG, defined as a primary glomerular disease, would accumulate data concerning clinical features, response to therapy, cause, and pathogenesis independent of well-defined diseases that may have similar glomerular deposits. However, not all accept this definition of ITG with its exclusions, and some pathologists, seeing a biopsy with organized glomerular immunoglobulin deposits, especially when the clinical information is too limited to make all the exclusions, may feel justified in diagnosing the smaller diameter fibrils as fibrillary glomerulopathy and the larger tubules with a hollow center as immunotactoid glomerulopathy. Consequently, the diagnoses of ITG and FGN will both contain a mixture of primary and secondary glomerular diseases, and by including patients with systemic diseases and lymphoproliferative disorders, the clinical characteristics of both groups will become a function of the underlying diseases (36,37). The validity and utility of this approach depends on the demonstration that the different ultrastructural appearances define discrete and mutually exclusive morphologic categories of glomerular disease and that the fibrillar and tubular forms of Congo red–negative organized glomerular immune deposits have specific and different clinical associations (41). Unless these differences are clearly apparent, the clinician, confronted by two entities that are similar clinically, pathologically, and biochemically and are differentiated only by the ultrastructural appearance of the deposits, may find this distinction unnecessary and confusing.

Clinical Implications of Fibril Size, Appearance, and Organization

When organized glomerular deposits are grouped by their ultrastructural appearance, the diagnosis of ITG is reserved for cases with larger, parallel tubules, and cases with smaller, randomly arranged fibrils are called fibrillary glomerulonephropathy/glomerulonephritis (FGN). The rationale for this distinction is that it allegedly provides a reproducible division with important and unique clinical implications (37,41,61,6369). However, Korbet et al (68) used ITG to describe patients with both types of deposits, and FGN more properly denotes glomerular diseases with fibrils seen by electron microscopy without regard to their biochemical composition (64,66,70). In spite of these problems, I will use these terms to consider the validity and utility of separating biopsies containing

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glomerular nonamyloid, organized immune deposits into two categories on the sole basis of the appearance of the deposits.

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Figure 20.7 Fibril diameter in 88 patients diagnosed with immunotactoid (fibrillary) glomerulopathy. (From

Korbet SM, Schwartz MM, Lewis EJ. The fibrillary glomerulopathies. Am J Kidney Dis 1994;23:751.

)

The morphologic features that reportedly discriminate between the tubules in ITG and the fibrils in FGN include cross-sectional diameter, lumens, and random versus parallel arrangements. Although fibril/tubule diameter is consistent within a biopsy and among biopsies from the same patient, there is a range of diameters from 10 to 49 nm () (Fig. 20.7). Generally, the fibrils of FGN have an average diameter from 18 to 22 nm, approximately twice the diameter of amyloid fibrils, and virtually all cases measure less than 30 nm (37,60,61,63,69). When Pronovost et al (59) defined ITG by fibril size larger than 30 nm, it composed only 6.5% of the 186 cases they reviewed. In contrast, when they defined ITG by focal parallel arrangement of the fibrils, it almost doubled its prevalence (12%). Some have argued that the morphologic definition of ITG also includes a “hollow,” electron-lucent tubular lumen, but the fibrils in many if not all cases of what has been called FGN also have an electron-lucent lumen (64,68). Bridoux et al (36) reported on 14 ITG patients with hollow-core microtubules in (focal) parallel arrays. In the four patients who did not have a disease that has been associated with organized glomerular immunoglobulin deposits including lymphoma, leukemia, or a MGUS, the microtubules measured 15 ± 6 nm in diameter. Using an arbitrary definition of the fibril morphology, one can separate some cases (FGN) from a much smaller number of cases (ITG), but there is considerable overlap between the two diagnostic categories. Using fibril size of 30 nm as the cutoff, Rosenstock et al (37) reported that 61 cases of FGN had a mean diameter of 20.1 nm ± 0.4 (range 13 to 29 nm) and 6 cases of ITG had a mean diameter of 38.2 nm ± 5.7 (range, 20 to 55 nm). Even if it were possible to separate ITG and FGN into mutually exclusive morphologic groups, there is no compelling reason to do so unless the ultrastructural features have significant clinical implications.

68,37) or lymphomas, leukemia, or MGUS (36) found no significant difference in the clinical features or demographics at presentation. In addition, the clinical outcome and response to therapy was either not different or the number of patients with ITG was too small to analyze. Pronovost et al () compared the demographics and clinical features of 186 patients with ITG and FGN. There was a slight female predominance, but there were no age differences. They found no difference in the prevalence of hypertension, hematuria, nephrotic syndrome, and renal insufficiency at presentation whether the diagnosis was established by fibril size (FGN up to 30 nm and ITG larger than 30 nm) or fibril arrangement (FGN random and ITG focally parallel). They also evaluated the association between FGN and ITG and lymphoproliferative disease. As might be predicted, patients with a serum or urine paraprotein and a lymphoproliferative disorder frequently (44%) had organized glomerular deposits of a tubular nature, as is seen in ITG. However, when patients with a paraprotein were excluded, the prevalence of neoplasia in both ITG and FGN was similar and low. The authors concluded that it was premature to subclassify ITG/FGN because of their similar clinical presentations, the similar prevalence of lymphoproliferative malignancy when patients with a paraprotein were excluded, and the insufficiency of biochemical and pathogenetic information to justify subclassification on the basis of fibril composition or mechanisms of fibrillogenesis (70

These considerations lead to the conclusion that there is too much overlap in fibril morphology to dichotomize the biopsies in a nonarbitrary manner, and the morphologic differences, which some believe to support a distinction between ITG and FGN, are of unknown significance. The clinical utility of this distinction is also in question because there are no consistent differences in clinical presentation, demographics, prognosis, or response to therapy related to fibril size, morphology, or organization, and when secondary causes of organized glomerular immunoglobulin deposits are excluded (including patients with a paraprotein), the prevalence of hematologic malignancy is low and similar. In my opinion, if it is to be clinically useful, pathologists should diagnosis ITG only after excluding diseases known to be associated with organized glomerular

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immunoglobulin deposits. Therefore, I consider ITG to be a primary glomerular disease characterized by deposits of immunoglobulin and complement that have variable electron microscopic appearances, and the diagnosis requires exclusion of diseases known to be associated with organized glomerular immune deposits. In the following discussion of the clinical findings, pathologic features, and outcome, I will refer to the entity as ITG regardless of the ultrastructural appearance of the deposits. However, when an author distinguishes between ITG and FGN, I will follow the article's convention in presenting the data.

Clinical Findings

ITG is an uncommon condition, but more than 200 cases have been reported as ITG or one of its synonyms since it was first described in 1977 (54). The clinical features have been the subject of several reviews and large series that summarize the data and give the primary references (59,60,63,64,68,69,70,71). Additionally, case reports and series have accumulated since the 5th edition of Heptinstall's Pathology of the Kidney (,37,53,72,73,74,75,76,7778,79). In a study restricted to biopsies with fibrils less than 30 nm in diameter, the prevalence was 0.8% of 3785 consecutive nontransplant renal biopsies (63). Another large biopsy series reported 60 biopsies with fibrils smaller than 30 nm (0.6%) and 6 biopsies with fibrils 30 nm or larger (0.06%) among 10,108 native kidney biopsies (37). The prevalence of ITG is similar to that of amyloidosis (63). Fogo et al (69) reported 32 cases of FGN (1.2%) and 52 cases of amyloidosis (2%) in 2649 biopsies over an 11-year period. In our series of adult patients with the nephrotic syndrome, ITG constituted 4% of the biopsies (13 of 340), and the prevalence of amyloidosis was similar (11 cases) (80).

The clinical presentation of ITG does not distinguish it from the other primary causes of proteinuria and the nephrotic syndrome (71), and this point was confirmed in a review of 186 patients with ITG and FGN (59). The disease presents in the fifth decade with an equal distribution between men and women (63,71), and a disproportionate number of the patients are White (37,59,63). All patients with ITG have proteinuria, and at the time of presentation, more than half have nephrotic syndrome. Despite the prominence of proteinuria and symptoms related to the nephrotic syndrome, some patients are frankly nephritic at presentation or develop rapidly progressive glomerulonephritis. Hypertension, hematuria, and renal insufficiency frequently accompany proteinuria (37,59,71). ITG is rare in children (78,81,82). By definition, there is no evidence of cryoglobulinemia, paraproteinemia, lymphoproliferative disorder, or plasma cell dyscrasia. Even though up to 19% of ITG patients have a positive antinuclear antibody, it is usually in low titer or in a speckled pattern (63,68), and those patients fulfilling the clinical criteria for systemic lupus erythematosus are excluded. With rare exceptions, clinical involvement is limited to the kidney.

Nonglomerular renal deposits and systemic involvement with organ dysfunction are very unusual. There are two reports of ITG in patients with pulmonary hemorrhage, and in one, pulmonary involvement was associated with rapidly progressive glomerulonephritis (83). Fibrillar deposits in the lung were identical to those in the kidneys in both cases (83,): The deposits stained for IgA in one case (83) and IgG in the other (84). Ozawa et al (85) reported a patient with glomerular and myocardial deposits of 8- to 12.4-nm fibrils that were positive for IgG and complement (C3) by fluorescence microscopy and were Congo red–negative.

Pathologic Findings

Light Microscopy

In the 43 cases of ITG that I have studied, the glomerular pathology generally reflects the distribution of the deposits (personal observation, 2005). Every case showed some degree of mesangial expansion by eosinophilic, PAS-positive material from a slight increase to massive deposits with glomerular distortion (Fig. 20.863,68,71) and other abnormalities, including irregularities, subepithelial projections (spikes), silver-negative defects (holes), and splitting (Fig. 20.9). These pathologic changes reflect the subepithelial and subendothelial location of the deposits and widespread infiltration of the GBM by deposits (see Electron Microscopy). Cases with diffuse spikes and holes or splitting were rare, and only three cases seriously suggested the diagnosis of membranous glomerulonephritis (Fig. 20.10). Mild mesangial hypercellularity (two to four cells per mesangial area) often accompanied mesangial expansion and GBM abnormalities (Fig. 20.11A), but mesangial hypercellularity was moderate to severe in only 5 of 43 cases (Fig. 20.11B). Two cases had prominent glomerular capillary thrombi (Fig. 20.12). Hyalinized and obsolescent glomeruli were a nonspecific but common finding in ITG: on average, one third of the glomeruli were hyalinized, and more than half of the glomeruli were hyalinized in 12 of 43 cases. The deposits in the mesangium and the GBM are periodic acid-Schiff (PAS)–positive and blue with the trichrome stain, and they are negative with the Congo red and thioflavin T stains for amyloid. There are no specific lesions of the tubules, interstitium, or blood vessels, but interstitial fibrosis and tubular atrophy are commensurate with the degree of glomerular obsolescence.

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Figure 20.8 Immunotactoid glomerulopathy.  Glomerulus showing mild expansion of the mesangium by PAS-positive material and a slight increase in mesangial cells. The GBM appears normal. (PAS, ×170.) B: Glomerulus with severe mesangial expansion. The capillaries are patent, and the GBM appears normal. (Methenamine silver–PAS, ×170.)

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Figure 20.9 Immunotactoid glomerulopathy. Glomerular basement membrane pathology. A: Focal thickening (arrows). (×350.) B: Diffuse spikes. (×550.) C: Basement membrane staining is irregular with mottling and well-defined holes. (×550.) (A–C

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Figure 20.10 Immunotactoid glomerulopathy. The basement membranes are diffusely thickened and have focal intense eosinophilia, reflecting widespread subepithelial, intramembranous, and subendothelial organized deposits. Also, the mesangium is expanded and shows segmental mild hypercellularity. (H&E, ×170.)

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Biopsies diagnosed as ITG or FGN are sometimes associated with significant glomerular inflammation including crescents, endocapillary proliferation, membranoproliferative glomerulonephritis, and segmental necrosis with neutrophil infiltration. Iskandar et al (63) reported crescents in 19% of 31 renal biopsies showing FGN, and crescentic involvement ranged from 10% to 80%. Fogo et al (69) found crescents in seven cases that involved from 13% to 75% of the glomeruli in 32 patients with FGN. Most were fibrous crescents, but in one case, there were active cellular crescents. In addition, there was a diffuse proliferative or lobular pattern of glomerulonephritis in 25 of 32 biopsies. In 60 patients with FGN (fibril diameter <30 nm), Rosenstock et al (37) found MPGN in 44% (27 cases) and diffuse endocapillary proliferative glomerulonephritis (DPGN) with leukocytic infiltration in 15% (9 cases). Thirty-one percent of 60 FGN cases had cellular or fibrocellular crescents, and they were most frequent in the DPGN group involving a mean of 25% of the glomeruli (range 0% to 57%). In the six patients with fibril diameter of 30 nm or more, three had MPGN and three had DPGN. None had crescents. In addition, there are isolated reports of ITG with a rapidly progressive course and crescents or necrosis in more than half of the glomeruli (76,83,87,88,89).

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When cryoglobulinemia, paraproteinemia, and systemic diseases were excluded, the 43 cases of ITG that I studied had less diffuse inflammation, and when necrosis was present, it was segmental and focal. Four biopsies had focal segmental glomerular necrosis superimposed on mesangial expansion and focal GBM thickening (Fig. 20.13). In two cases, one glomerulus was involved, and in two cases, two glomeruli showed necrosis. A crescent was associated with an area of necrosis in one case (Fig. 20.14), and crescents were seen in the surviving glomeruli in an end-stage kidney showing extensive glomerular sclerosis. None of the remaining 38 biopsies had active, cellular crescents or glomerular necrosis.

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Figure 20.11 Immunotactoid glomerulopathy. A: Mild mesangial proliferation with three to six cells per mesangial area. B: Moderate proliferation with five to nine cells per mesangial area. The capillaries are patent and the GBM appear normal in both photographs. (A and B, H&E, ×170.)

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Figure 20.12 Immunotactoid glomerulopathy. Glomerular thrombi. The capillaries contain hyalin thrombi that stained for IgG, but the thrombi were fibrin-negative by fluorescence microscopy. By electron microscopy the capillaries contained organized immune deposits. Note that the glomerular basement membranes are split. (Methenamine silver–PAS; ×550.)

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Figure 20.13 Immunotactoid glomerulopathy. There is a segmental area of glomerular necrosis with destruction of capillaries, proliferation of the overlying epithelial cells, and adhesion to Bowman's capsule. The uninvolved glomerular tuft shows mesangial expansion with minimal hypercellularity, patent capillaries, and normal basement membranes. (PAS, ×170.)

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Figure 20.14 Immunotactoid glomerulopathy. A: A small crescent in Bowman's space overlies a damaged glomerular segment. The uninvolved portion of the glomerulus shows mesangial expansion and normal basement membranes. (PAS, ×170.) B:arrow) in the necrotic glomerular segment in the same glomerulus seen in (A). (Methenamine silver–PAS [Jones], ×350.)

Immunohistopathology

The pattern of glomerular immunoglobulin and complement deposition in ITG is variable, and it reflects the mesangial and GBM locations of deposits seen by electron microscopy (60,63,69,71). Most commonly, both mesangial and GBM deposits are present, but in a few cases, the deposits are isolated to the GBM or the mesangium. The mesangial deposits are either discrete and granular (Fig. 20.15A) or diffusely expand the mesangium and focally extend into the basement membrane (Fig. 20.15B). The GBM deposits are usually irregular, discontinuous linear, and granular (Fig. 20.16A), or ribbonlike, but a few cases show diffuse granular staining (Fig. 20.16B). Until recently, there were no reports of tubular basement membrane, interstitial, or vascular deposits. Adeyi et al (75) reported on two patients with polyclonal deposits of IgG in the glomeruli and along the tubular basement membranes. The histochemical stains for amyloid were negative. The fibrils measured 28 nm in one case, and the second had 30-nm fibrils in the glomeruli and 15-nm fibrils in the tubular basement membranes.

In a review of the cases of ITG reported up to 1994, IgG was the most frequent immunoglobulin seen in the deposits (103 of 110 reported cases, 94%). IgA was found in 29 of 101 (29%), IgM in 62 of 102 (60%), and C3 in 99 of 103 (96%). The IgG usually contained both κ and λ light chains (62 of 86 cases, 72%) (64,71). Two large series (37,63) confirmed this composition of the deposits, and

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they both demonstrated that IgG and C3 had the strongest staining intensity. Monoclonal immunoglobulin deposits were present in 16 of 86 cases (19%) of ITG studied with light chain antisera, and κ light chain restriction was in all reported cases, usually in combination with γ heavy chain (,34,35,46,,68,90,,9293,94,95). Rosenstock et al (37) reported a case of FGN with λ light chain restriction. I have seen a similar case, but it was complicated by the presence of an IgGκ paraprotein (see above, Paraproteinemia). There are case reports in which the glomerular deposits contained IgAλ (73) and IgMκ (5). In two studies that dichotomized the biopsies on the basis of fibril size (<30 nm versus 30 nm or larger) (37) or appearance (fibrillary versus tubular) (), the immunoglobulin distribution was similar in both groups with IgG dominance. Iskandar et al (63) studied the IgG subgroups in 28 patients with fibril diameters less than 30 nm (mean 22.2 nm ± (7.4). The deposits were restricted to IgG subgroup 4 (IgG4). This was in contrast to the predominance of IgG1 and IgG3 in the glomerular deposits of control patients with diffuse lupus glomerulonephritis and was similar to that seen in control patients with idiopathic membranous glomerulonephritis. Monoclonal IgG3κ was reported in a case with 35-nm microtubular deposits (67).

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Figure 20.15 Immunotactoid glomerulopathy. Mesangial deposits. A: Immunoglobulin G (IgG) is deposited in a pure mesangial pattern. Note the total sparring of the glomerular capillary walls. Light microscopic changes were also confined to the mesangium and consisted of PAS-positive expansion. B: There is massive mesangium expansion by irregularly staining deposits of immunoglobulin G (IgG). The deposits also focally involve the glomerular basement membranes.

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Figure 20.16 Immunotactoid glomerulopathy. Glomerular basement membrane deposits. A: Immunoglobulin G (IgG) is seen as discontinuous linear and focal granular staining. The mesangium is largely uninvolved. B: There are massive granular deposits of immunoglobulin G along the basement membranes and in the mesangium. (A and B, fluorescein isothiocyanate conjugated rabbit anti-human IgG, ×170.)

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The relationship between monoclonal glomerular deposits and fibril morphology and size is inconstant. Most of the reported cases with monoclonal glomerular deposits do not have large-diameter microtubular deposits. At presentation, 13 of the 65 biopsies studied with immunoglobulin light chain antisera showed light chain restriction. This was usually IgGκ although other heavy and light chain specificities are described. On the one hand, 12 of the 13 cases with monoclonal deposits were associated with smaller diameter (<30 nm), randomly arranged microfibrils/microtubules, and in only one case were the associated microtubules 30 nm or larger and closely packed (68). An additional ten biopsies with organized microtubules 30 nm or larger were not studied for light chains (9 biopsies) or had no restriction (1 biopsy).

Electron Microscopy

The extracellular deposits in ITG are elongated, nonbranching fibrils or tubules (6,3759,60,64,68,70,71). They do not show periodicity or substructure, and their localization at the same sites as immune deposits seen by fluorescence microscopy implies that they contain immunoglobulins and complement as principal components. Additional ultrastructural findings include mesangial expansion and hypercellularity, basal lamina splitting, mesangial circumferential extension, and diffuse glomerular epithelial cell (GEC) foot process effacement.

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Figure 20.17 Immunotactoid glomerulopathy. The mesangium (MES) is expanded by vague electron-dense deposits, which spare the GBM. (Uranyl acetate and lead citrate, ×8600.) CAP, capillary lumen. Inset: At higher magnification, the mesangial deposits comprise randomly arranged fibrils that measure 21.3 ± 4 nm in diameter. (Uranyl acetate and lead citrate, ×28,800.) (From

Korbet SM, Schwartz MM, Rosenberg BF, et al. Immunotactoid glomerulopathy. Medicine 1985;64:228.

)

Organized deposits are found throughout the glomerulus, but the mesangium is nearly always involved (6,60,61,63,64,71) (Fig. 20.17). In approximately 25% of the cases, only the mesangium is involved, but usually mesangial and basal lamina deposits are found together. The basal lamina deposits have a predilection for the lamina densa and the lamina rara externa (32,60,93,9495,96). In some cases subepithelial deposits are discrete, isolated, and extensive (Fig. 20.18). In a few instances the subepithelial fibrils are oriented perpendicular to the basal lamina and resemble spicular amyloid (54,68,92). In other cases there are prominent subendothelial deposits that encroach on the lumen as pseudothrombi (58,63,68,93,94,,96) (Fig. 20.19). New layers of basal lamina form over both

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the subendothelial and subepithelial deposits. In other instances, the GBM appears diffusely infiltrated and replaced by fibrils (Fig. 20.20).

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Figure 20.18 Immunotactoid glomerulopathy. Deposits of 35.4 ± 2 nm in diameter tubules occur as discrete subepithelial masses (asterisks) and as masses incorporated into the capillary wall and covered by newly formed GBM (arrow). CAP, glomerular capillary lumen. EPI, glomerular epithelial cell. (Uranyl acetate and lead citrate, ×12,500.) Inset: The immunotactoids are seen as closely packed tubules in longitudinal and cross-sectional arrays demonstrating their regular diameter, thick walls, and electron-lucent core. (Uranyl acetate and lead citrate, ×35,000.) (From

Korbet SM, Schwartz MM, Rosenberg BF, et al. Immunotactoid glomerulopathy. Medicine 1985;64:228.

)

The appearance of the fibrils and their state of organization varies from case to case, but within a biopsy and between biopsies performed in the same patient at different times, the deposits are similar. The reported microfibril/microtubule diameter varies from the size of amyloid (9 to 11 nm) to greater than 50 nm, and the estimated length ranges from 1000 to 1500 nm (Fig. 20.7). The cross-sectional appearance varies from a solid dot to tubules with either a thin or a thick wall (Fig. 20.21). A lucent center or a lumen is easily seen in tubules with a diameter of 30 nm or more, but careful examination often reveals a lumen in fibrils with a diameter smaller than 30 nm (68). High-resolution studies have failed to demonstrate either periodicity or substructural organization in the deposits (6). In most cases the fibrils/tubules are randomly arranged in the mesangium and in the GBM, but in some cases with larger diameter tubules, the deposits are seen in a tightly packed, parallel arrangement (61,67,69,94,97). Granular unorganized deposits have been seen separately from the organized deposits or intermixed with them in the GBM and the mesangium (6,54,60,61,62,69,90,92,93,98), suggesting that they are only partially organized. However, Yang et al (98) studied seven patients with glomerular Congo red–negative, 15- to 20-nm microfibril deposits by protein A gold immunoelectron microscopy, and although they noted nonfibrillar electron-dense areas in the biopsies, positive staining for IgG, both light chains, and C3 were confined to the fibrils. In contrast to organized deposits in immune complex diseases such as SLE, the immune reactants were confined to the microfibrils in the cases studied, and the nature of nonfibrillar electron-dense deposits remained unelucidated.

Extraglomerular deposits are rare in ITG. In a few cases, deposits are described in the tubular basement membranes or the interstitium (6,60,67,68,75) (Fig. 20.22). In association with typical glomerular pathology, organized immunoglobulin deposits have been described in the liver

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(85) and the lung (83,84). In these cases there was clinical evidence of extrarenal disease, but when clinically uninvolved organs were studied, deposits were not present (92). In an autopsy study of a patient with ITG, random sections of liver, spleen, heart, and skin did not contain organized deposits and the sections were Congo red–negative. Furthermore, there was no evidence of plasma cell dyscrasia or lymphoproliferative disease (68).

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Figure 20.19 Immunotactoid glomerulopathy. Glomerular capillary almost occluded by a large subendothelial deposit and a luminal thrombus separated by the preserved endothelium (arrows). (Uranyl acetate and lead citrate, ×5300.) Inset: At higher magnification, deposits comprise tightly packed tubules with an external diameter of 48.9 nm beneath the glomerular basement membrane (GBM), and they are separated from similar deposits in the capillary lumen by the endothelial cell (asterisks

Korbet SM, Schwartz MM, Rosenberg BF, et al. Immunotactoid glomerulopathy. Medicine 1985;64:228.

)

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Figure 20.20 Immunotactoid glomerulopathy. Immunotactoids, measuring 22.8 ± 3 nm, are seen as solid dots in cross section and elongated fibrils in the subepithelial and subendothelial regions of the capillary wall, penetrating and displacing the substance of the basal lamina. EPI, glomerular epithelial cell; CAP, capillary lumen. (Uranyl acetate and lead citrate, ×30,000.) (From

Korbet SM, Schwartz MM, Rosenberg BF, et al. Immunotactoid glomerulopathy. Medicine 1985;64:228.

)

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Figure 20.21 The spectrum of immunotactoid fibril diameter. Immunotactoids of large (35.4 nm) and small (21.3 nm) diameter shown with amyloid (center) at the same magnification for comparison. On the left are the thick-walled tubules seen on four successive biopsies of one patient. Illustrated on the right are the 21.3-nm microtubules characteristic of most cases of ITG. Arrowheads indicate an electron-lucent core in amyloid (center) and immunotactoid fibrils (right). Uranyl acetate and lead citrate, ×118,000. (From

Korbet SM, Schwartz MM, Rosenberg BF, et al. Immunotactoid glomerulopathy. Medicine 1985;64:228.

)

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Figure 20.22 Immunotactoid glomerulopathy. Extraglomerular immunotactoids are present in the interstitium, concentrated around a peritubular capillary (PTC). This feature was seen in only one of four biopsies from this patient. PCT, proximal convoluted tubules. (Uranyl acetate and lead citrate, ×19,000.) (From

Korbet SM, Schwartz MM, Rosenberg BF, et al. Immunotactoid glomerulopathy. Medicine 1985;64:228.

)

Etiology and Pathogenesis

The etiology and pathogenesis of ITG are unknown, and there are no clinical or experimental data to suggest that deposits with different-sized and organized fibrils/tubules have separate causes or pathogenetic mechanisms. Any proposed pathogenic mechanism must account for three general features of ITG, however: lymphocytes or plasma cells produce the immunoglobulins found in the deposits; the precursors reach the kidney via the circulation; and the deposits are predominant in the glomeruli. The first two features suggest that the pathogenesis of ITG is similar to that of cryoglobulinemia or monoclonal gammopathy. Because cryoglobulins and paraproteins constitute exclusions from the diagnosis of ITG, the immunoglobulin must circulate in quantities that escape routine testing. It is also possible that non–cold precipitable immunoglobulins or immune complexes that are able to form organized deposits in the glomerulus explain this phenomenon. Additionally, B-cell or plasma cell neoplasia is not a necessary condition because the glomerular deposits are polyclonal in most cases. The third feature implies a role for local factors in fibrillogenesis. For example, plasma concentration produced by glomerular ultrafiltration may be a prerequisite for fibril formation.

The ultrastructural similarities between ITG and amyloidosis suggest that the pathogenesis of the two conditions is similar, and the morphologic and immunologic heterogeneity of the glomerular deposits in ITG may be the result of several mechanisms and precursors analogous to amyloid fibril formation. Yang et al (98) studied the relationship between amyloid and ITG and showed that in their patients the fibrils contained amyloid P component in addition to γ heavy chain and both κ and λ light chains and C3. GBM matrix proteins (type IV collagen, heparan sulfate proteoglycan, fibronectin, and fibrillin) were not present. The presence of amyloid P component suggests that the fibrils in ITG form in an analogous fashion to amyloid, but the final product does not form a beta pleated sheet and thus, is Congo red–negative. Casanova et al (92) stained the fibrils for IgG, both light chains, and C3, but they did not contain amyloid fibril proteins. In both studies (9298), protein A gold immunoelectron microscopy demonstrated that the positive elements were localized to the fibrils, leading to the conclusion that all the pathologic immunoglobulins were present in an organized state. Neither group studied examples of ITG with tubules 30 nm or more in diameter.

88) reported a unique case in which biochemically identical fibrils were seen in the glomeruli and in a serum precipitate that formed after four months at 4°C. The fibronectin content of the fibrils, seen in the glomeruli and in the serum precipitate, suggested that fibronectin plays a role in fibrillogenesis. Although that remains a possibility in their unique case, the authors failed to find fibronectin in the glomerular deposits in other patients with FGN (9867,,71).

Pathogenic speculation concerning ITG has focused on systemic factors such as the characteristics of normal or pathologic immunoglobulins whose properties favor glomerular precipitation and fibrillogenesis. Recurrent disease following renal transplantation supports a role for systemic factors (37,5559,,99). However, the absence of a demonstrable paraprotein and a population of neoplastic plasma cells or lymphocytes suggest that local glomerular factors are involved. The CD2-associated protein (CD2ap) knock-out mouse provides support for defective glomerular function in ITG and localizes the defect to the podocyte (100,101). CD2ap is an 80-kD protein found in the specialized junction between T lymphocytes and antigen-presenting cells (100,102), and it is also found throughout the developing and mature kidney (100). In the glomerulus, CD2ap binds to the cytoplasmic domain of nephrin, a key component of the podocyte slit diaphragm (100), where it contributes to the filtration barrier. CD2ap knock-out mice have congenital nephrotic syndrome and compromised immune function, and they die of renal failure 6 to 7 weeks after birth. The podocytes show pathologic changes (103), and the glomeruli have mesangial and subendothelial deposits of parallel arrays of tubules seen by electron microscopy (103). Although the composition of the tubules is unknown, the ultrastructural pathology is similar to that seen in ITG in human beings. Thus, it may be that glomerular deposits in ITG are secondary to acquired defects in critical podocyte cellular functions involved in the clearance of filtered and retained immunoglobulins. In addition, the organized nature of the deposits suggests that physicochemical homogeneity of the precursor molecules remains an important

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distinguishing pathogenetic feature between ITG and other primary immunoglobulin-mediated glomerular diseases in which the deposits are not organized.

Clinical Course, Prognosis, Therapy, and Clinicopathologic Correlations

Clinical Course and Prognosis

Renal insufficiency is a presenting feature in 50% of patients with ITG, and the disease progresses to end-stage renal disease in almost half the cases within 2 to 4 years of follow-up (37,59,6364,69). Because systemic diseases or hematologic disorders associated with organized glomerular ultrastructural deposits are exclusions, the patients do not develop signs or symptoms related to these conditions. The renal course with persistent proteinuria, frequently in the nephrotic range, and the progressive loss of renal function is similar to that seen in other primary forms of glomerular disease.

Therapy

There are case reports that suggest that treatment with prednisone and various immunosuppressive agents induces a reduction of protein excretion (74), but no statistically supported clinical trial has been published. The reports of therapeutic responses emphasize the critical importance of the definition of ITG. In one case, a patient with a malignant lymphoma reduced the level of proteinuria while being treated with alternate-day prednisone (4636). In these cases, reversal of renal disease is a known result of therapy of chronic lymphocytic lymphoma and leukemia (44). A patient with de novo ITG and hypocomplementemia following renal transplantation completely reversed massive subendothelial and focal mesangial immunotactoid deposits while on antirejection therapy (104). Although there were organized glomerular deposits in this case, the clinical setting and the presence of hypocomplementemia disqualify this case for the diagnosis of typical ITG. Therefore, treatment with steroids alone, steroids with plasma exchange, and steroids with cyclophosphamide have not been effective or offer limited benefit in the treatment of patients with ITG when underlying diseases that may respond to such treatment (cryoglobulinemia, lymphoproliferative malignancy, and systemic lupus erythematosus) are excluded (37,70,71).

Patients with ITG frequently present with renal insufficiency, and they have a progressive course that does not respond to current therapy. Because they generally do not have systemic involvement, their prognosis, independent of renal survival, is quite good. A limited number of patients with ITG have received renal transplants, and the disease recurred with identical immunopathology and ultrastructural pathology in the grafts and the native kidneys in approximately half of the cases (37,55,59,60,99). Although recurrent disease in one patient occurred 21 months after transplantation and led to graft loss 3 years later (100), graft function remained adequate after 5 to 11 years of follow-up in the others (37,55,59,6099). There are three reports of de novo ITG following renal transplantation (37,83,104). Therefore, renal transplantation is appropriate therapy for patients with ITG that has reached end stage, and this good result is in contrast with the poor patient survival in primary amyloidosis (64).

 

The clinicopathologic correlation with the most potential is also the most controversial. It has been suggested that the tubular deposits with a lucent core and at least focal organization into parallel arrays (usually >30 nm) are associated with hematologic malignancy (37,41,46,69) and dysproteinemia (31,35,41,69), and smaller (<30 nm) randomly arranged fibrils are not. As Korbet et al (68,71) and others (59) have shown, this association is dependent on including patients with paraproteinemias in the diagnosis of ITG. When paraproteinemias are excluded, the prevalence of hematologic malignancy is equally low in patients with deposits smaller than 30 nm and in those with deposits 30 nm in diameter and larger. Nevertheless, the literature contains at least 47 cases reported with the diagnosis of ITG or one of its synonyms and an antecedent hematologic malignancy or monoclonal serum immunoglobulin (32,34,36,41,46,52,68,69,91,105). Twenty-five of these cases, including one reported by Korbet et al (68), had fibrils that were less than 30 nm in diameter and randomly oriented, demonstrating that the association with hematologic neoplasia is not limited to cases with larger microtubular deposits (106). In contrast, the glomeruli in the index case of ITG (67) contained monoclonal deposits of IgG that appeared as large-diameter (35.4 nm), closely packed tubules by electron microscopy. Repeated evaluations of the patient and his serum and bone marrow never had clinical or serologic evidence of dysproteinemia, cryoglobulinemia, lymphoproliferative disorder, or systemic disease. He progressed to end-stage kidney disease and died of unrelated causes after a clinical course that covered almost 18 years. There is a known association between hematologic malignancies and monoclonal gammopathy and organized glomerular deposits (see above), and the diagnosis of ITG should not include these patients.

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More than 50% of patients with ITG progress to end-stage renal disease, and identification of those who will develop progressive renal disease has been a focus of clinical study. Korbet et al (68) followed 11 patients with ITG (mean fibril diameter <30 nm in 8 and 30 nm or more in 3) for a mean of 52.6 months (range 22 to 94 months), and 6 progressed to a serum creatinine greater than 5.0 mg/dL. Male gender, poorly controlled blood pressure, and nephrotic-range proteinuria were more prevalent in the patients who progressed compared with those who did not progress. The authors noted that the two patients with strictly mesangial involvement were in the nonprogressive group. Pronovost et al (59) stratified 25 patients with ITG/FGN (defined by fibril diameter and arrangement) into three groups according to the slope of 1/serum creatinine (1/Cr). Ten patients had no or slow progression (1/Cr = –0.103); nine had intermediate progression (1/Cr = 0.121); and six had rapid progression (1/Cr = 0.466). The three groups did not differ in age, the prevalence of hematuria and proteinuria, or the serum creatinine at presentation. Although patients with more rapid progression of renal dysfunction had a greater prevalence of nephrotic syndrome and worse hypertension, the differences were not statistically significant. Rosenstock et al (37) analyzed outcome in 56 patients with FGN (fiber diameter <30 nm), and after a mean of 23 months (range 0 to 128 months), 25 progressed to end-stage renal disease. The authors reported diverse patterns of glomerular pathology in FGN, and patients with pure mesangial and membranous patterns (times to end-stage renal disease 80 and 87 months, respectively) had longer renal survival than patients with membranoproliferative, diffuse proliferative, and diffuse sclerosing glomerulonephritis (times to end-stage renal disease 44, 20, and 7 months, respectively). In a univariate analysis of presenting clinical and pathologic findings, the histologic subtype, nephrotic syndrome, severity of interstitial disease, presence of crescents, percent crescents, hematocrit, level of protein excretion, serum creatinine, and the percentage of sclerotic glomeruli correlated with outcome. However, multivariate analysis showed that the initial serum creatinine and the severity of interstitial disease were the only clinical and pathologic features that independently predicted progression to end-stage renal disease.

Diseases with Congo Red–Negative (Nonamyloid) Non–Immunoglobulin-Derived Organized Deposits

Diseases with Congo red–negative deposits of diverse biochemical composition constitute a third group with organized glomerular deposits. There are collagen fibers in the thickened glomerular basal lamina in the nail-patella syndrome and in the expanded subendothelium and mesangium in collagenofibrotic nephropathy (type III collagen nephropathy)Chapter 11). There may be deposits of fibrin in inflammatory glomerular diseases, and the polymerized fibrin usually forms amorphous electron-dense masses. Rarely, there are fibrin tactoids with typical periodicity (Fig. 20.23). The mesangium in diabetic glomerulosclerosis may contain 10- to 20-nm-diameter fibrils (Fig. 20.24). They are the postulated result of advanced glycosylation end product–related cross linking of normal matrix proteins (23,107) (see ). Fibronectin glomerulopathy is a rare hereditary disease with glomerular fibronectin deposits that sometimes form organized deposits (see below).

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Figure 20.23 Fibrin tactoids from a patient with chronic glomerulonephritis. Polymerized fibrin forms electron-dense, elongated masses with characteristic periodicity. (Uranyl acetate and lead citrate, ×30,000.)

Churg and Venkataseshan (66) reported three cases of glomerulopathy with Congo red–negative deposits that did not contain immunoglobulin, complement, or fibronectin. Electron microscopy demonstrated mesangial and tubular basement membrane fibrils measuring from 13 to 20 nm in diameter. The authors reported the cases to warn physicians of the possibility that a biochemical spectrum of organized deposits, including presently unidentified substances, may cause fibrillary glomerulonephritis. They used the term  to indicate the class of diseases with fibrillary deposits rather than a specific disease.

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Ferluga et al (108) reported a case of advanced diabetic nodular glomerular sclerosis that also had prominent subendothelial deposits of microtubules, 67 nm in diameter, with similar localization of IgG, IgM, κ, λ, C3, and fibrin. The patient had an IgG-IgM cryoglobulinemia (200 mg/L) that provides an alternative explanation for the organized deposits. However, as our experience with glomerular disease with organized deposits accumulates, it is predictable that further biochemically specific forms of fibrillary glomerulonephritis will be recognized (109,110), further clinical associations will be recognized (878), and cases with more than one population of organized deposits will be reported (39).

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Figure 20.24 Diabetes mellitus. The patient was a 25-year-old man with insulin-dependent diabetes mellitus for 9 years and proteinuria for 2 years. The mesangium was diffusely expanded by PAS-positive matrix, and there was diffuse linear staining of the GBM for IgG. The mesangium, underlying the capillary lumen (CAP), contains randomly arranged, 16-nm tubules that have an electron-lucent center in cross section (arrows). MC, mesangial cell. (Uranyl acetate and lead citrate, ×70,000.) (From

Korbet SM, Schwartz MM, Lewis EJ. The fibrillary glomerulopathies. Am J Kidney Dis 1994;23:751.

)

Fibronectin Nephropathy

Fibronectin nephropathy (FN), a disease with an autosomal dominant mode of inheritance, presents with proteinuria and slowly progressive loss of renal function. It was first reported as an atypical form of lobular glomerulonephritis with massive subendothelial and mesangial, focally fibrillar, electron-dense deposits that did not stain for immunoglobulins and complement (,111,112,113). Once fibronectin was identified as a major component of the deposits (66,114,115), the initially identified families were restudied, and the deposits were shown to contain fibronectin (116). Since the last edition of Heptinstall's Pathology of the Kidney, further cases have accumulated (117,118).

66,114,116) were 29.4 ± 15 years old at the time of diagnosis. All but two of the patients (66) had an affected first-degree relative, and the disease presented in parents and children of either sex and in multiple siblings. Proteinuria was the most common presentation (26 of 28), and in 12 patients it was in the nephrotic range (at least 3 g/24 hours). Twelve of 19 patients had microscopic hematuria, and mild hypertension was present in 11 of 19 patients. There were no consistent serologic abnormalities, and fibronectin levels were normal. Renal function was initially abnormal (elevated serum creatinine) in 5 of 21 patients. Despite persistent high-grade proteinuria, after 6.6 ± 4.2 years of follow-up, only 5 patients reached end-stage renal disease and required dialysis. However, 13 affected family members in one large kindred progressed to end-stage renal disease (119). Four patients received renal transplants, and 1 had a recurrence 27 months posttransplantation that progressed to graft failure.

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light microscopic change is glomerular enlargement and lobulation resulting from PAS and trichrome-positive mesangial deposits and mild mesangial proliferation (Fig. 20.25). This process displaces the glomerular capillaries to the periphery of the lobule and decreases their luminal diameters. With the Jones stain, the preserved GBM is usually at the periphery of the thickened capillary wall, and focal areas of duplication and subepithelial spikes are inconstant (112). There are no specific changes in the renal tubules, interstitium, and blood vessels. Special stains for amyloid are negative. By immunofluorescence microscopy, the glomeruli do not consistently stain for immunoglobulin or complement components. However, one case (111) did have intense mesangial and parietal staining for IgG and C3, and two patients (116) had positive staining for IgG, IgM, C3, and fibrinogen. In contrast, immunohistologic stains for fibronectin are strongly positive in all cases in the same mesangial and subendothelial location as the PAS-positive deposits. The most consistent ultrastructural finding is large (giant), mesangial and subendothelial electron-dense deposits that mirror the location

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of the PAS-positive, fibronectin deposits (Fig. 20.26). The GBM is usually normal and not directly involved (114,), but subepithelial and intramembranous deposits were seen in one family (112). Extraglomerular deposits are infrequent, but they have been described in the basement membrane of Bowman's capsule (112) and the tubular basement membrane (113). The electron-dense deposits are predominantly amorphous and granular, but they may contain electron-lucent areas and scattered, focal fine filaments 10 to 14 nm in diameter (112,114,115,116). The morphology of the deposits falls between the highly organized fibrils derived from mutant protein precursors seen in hereditary amyloidosis and the amorphous, infrequently fibrillar deposits of abnormal light chains in MIDD (see Chapter 28

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Figure 20.25 Hereditary glomerulopathy with fibronectin deposits. The glomerulus shows massive mesangial expansion by intensely PAS positive deposits that were silver- and Congo red–negative. Note the capillaries remain patent although reduced in size at the periphery of the expanded lobules. Kidney biopsy from a 22-year-old man with a strong family history of renal disease and proteinuria of 604 mg/24 hours and normal renal function. (PAS, ×235.) (Photomicrograph prepared from material supplied by Dr. Daniel D. Sedmak.)

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Figure 20.26 Hereditary glomerulopathy with predominant fibronectin deposits. Glomerulus showing massive mesangial (MES) electron-dense deposits. Although there were focal subendothelial electron-dense deposits, the capillary (CAP) illustrated is free of deposits. (Uranyl acetate and lead citrate, ×6250.) Inset:

Fibronectin is a multifunctional, extracellular matrix glycoprotein that is active in cellular adhesion and migration. Fibronectin is produced locally in the glomerulus by mesangial cells (cellular fibronectin), and the liver synthesizes fibronectin isoforms that circulate (plasma fibronectin). Upregulation of fibronectin production occurs in diverse glomerular diseases (120). Massive glomerular accumulation of plasma fibronectin, the central pathogenetic event in FN, implies that the precursor is derived from the circulation (114,116), but plasma levels of fibronectin are not elevated (115). Therefore, plasma fibronectin accumulates because either the clearance mechanism is faulty or the fibronectin is in a form that frustrates normal clearance mechanisms. Because other extracellular matrix proteins and immunoglobulins are inconstantly present in the deposits (114,116), a general defect of mesangial clearance is unlikely. Haplotype analysis in a 197-member pedigree with 13 relatives developing end-stage renal failure from the disease excluded mutations in fibronectin as the cause of the glomerulopathy (121). Although the gene has not been identified, Vollmer et al (122) postulated a genetic defect in a circulating factor that binds to fibronectin and leads to its glomerular retention. This is the apparent mechanism of glomerular localization of fibronectin in the uteroglobin knock-out mouse (123), but uteroglobin has been excluded from the pathogenesis of fibronectin glomerulopathy (124) in human beings. Vollmer et al (124) mapped the gene to a 4.1-cM interval on chromosome 1q32, and they propose a candidate gene from the regulation of complement activation cluster that is localized to this region. Interestingly, amyloid P component has been demonstrated in the deposits of one patient with FN (114), an observation that may explain the fibrillar organization seen in some cases.

References

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