Морф. изменения в почках при плазмоцитоме.-1

Figure 18. Light chain deposition disease. Transmission electron microscopy. Light-chain deposits with a powdery appearance along tubular basement membrane (uranyl acetate and lead citrate stain, original magnification 7500).

Figure 19. Light chain deposition disease with ‘‘minimal-change’’ appearance by light microscopy. Transmission electron microscopy. Gold particles are in capillary lumina and predominantly in the subendothelium, indicating the presence of light chains. There was no labeling for light chains, confirming monoclonality and supporting the diagnosis (uranyl acetate and lead citrate stain, immunogold labeling for light chains, 10-nm gold particles; original magnification 7500).

Among the glomerular expressions, ‘‘minimal’’ change, mesangioproliferative (Figure 8), membranoproliferative, and crescentic patterns have been documented in light chain deposition disease.5,10,12,46 These morphologic patterns are easily conceptualized as occurring as a result of the interplay of 2 growth factors: platelet-derived growth factor , promoting mesangial cell proliferation, and trans-

forming growth factor , responsible for matrix deposition.47 Because the morphologic expressions are by no means specific for these disorders, other generic descriptive diagnoses may be rendered, and the association with an underlying neoplastic plasmacytic process may not be recognized.

Nodular glomerulosclerosis represents the most recognized manifestation of light and heavy chain deposition disease (Figure 9, A).5,9,48 The mesangial nodules may be focal and small in the early stages of nodular glomerulosclerosis (Figure 10). The glomerular morphology in light and heavy chain deposition disease is similar, although cellular proliferation is in our experience more pronounced in heavy chain deposition disease (Figure 11). Secretion and activation of transforming growth factor produced by mesangial cells, leading to an increase in mesangial matrix rich in tenascin,49,50 is responsible for the mesangial nodularity.

When comparing the typical appearance of nodular glomerulosclerosis in light/heavy chain deposition disease with that of diabetic nephropathy, there are some differences that may be helpful in suggesting the correct diagnosis. The mesangial nodules in light and heavy chain deposition disease tend to be uniform in size in all glomeruli, whereas in diabetic nephropathy they are commonly irregular in distribution and vary in size and shape in a given glomerulus and among different glomeruli. A peculiar thickening of tubular basement membranes resulting from the deposition of monotypic light chains is also a very helpful finding in making a diagnosis of light or heavy chain deposition disease (Figure 9, B). Hyaline caps and capsular drops, as well as hyalinosis in afferent and efferent arterioles are features characteristic of diabetic nephropathy.

An important differential diagnosis is the recently recognized idiopathic nodular glomerulosclerosis, which is not associated with light or heavy chains or diabetes mellitus.51 Morphologically, this condition is identical to light and heavy chain deposition disease but lacks immunofluorescence and ultrastructural features associated with these conditions. Its diagnosis is essentially made when diabetic nephropathy can be excluded based on clinical and laboratory data. The pathogenesis of the idiopathic type of nodular glomerulosclerosis remains speculative, but the combined effect of hypertension and smoking has been suggested to play an important role.51

Although the glomerular manifestations are similar to those seen in diabetic nephropathy by light microscopy, immunofluorescence and electron microscopy should provide crucial additional information that allows establishing an unequivocal diagnosis in the great majority of cases. Typically, linear staining for the involved light (usually) or heavy (most commonly ) chain is present along peripheral capillary walls and in the mesangium in glomeruli and along tubular basement membranes (Figure 12). Staining can also be noted outlining Bowman capsule, in the interstitium proper, and in the vasculature. 4 is overrepresented in light chain deposition disease.

However, there are challenges in association with proper interpretation of the information that is obtained from these 2 diagnostic techniques. It is essential that pitfalls that may be encountered be understood fully. Because the abnormal light and heavy chains are often truncated in tissue deposits, the commercially available antibodies may not be able to pick them up. Therefore, no staining for

Figure 22. Light chain amyloidosis. Intense red staining is elicited when the Congo red–stained section is viewed under fluorescence light where amyloid deposits are present (Congo red stain, fluorescein gate; original magnification 250).

and light chains in the renal biopsy does not rule out these conditions. Patients with combined diabetic nephropathy and light/heavy chain deposition disease are also difficult to diagnose. The glomerular milieu in these patients can be such that commercially available antibodies to light and heavy chains may not detect antigenic sites in the deposited abnormal light and heavy chains (unpublished data, March 2000). The use of antibodies to specific light-chain subtypes increases the ability to detect deposits of abnormal light chains in light and heavy chain deposition disease. Demonstration of absence of CH1 (most common), CH2, or hinge region epitopes of the heavy chain in the renal glomeruli using antibodies to these regions can further confirm a diagnosis of heavy chain deposition disease.9,42,43

The ultrastructural features associated with lightand heavy-chain deposits in the renal parenchyma are also variable. The electron density associated with the punctate, powdery light–, and heavy-chain deposits can vary (Figures 13 through 15). In some instances, the deposits are very subtle (Figure 13, A) and can be easily missed, and in others they are so massive that they may be confused with immune complexes.52 Light-chain deposits are typically in subendothelial zones along peripheral capillary walls and/or in mesangial areas. However, the deposits may also be located on top of the lamina densa of the glomerular basement membranes, mimicking dense deposit disease53 (Figures 16 and 17, A), or on the subepithelial side (Figure 17, B), albeit rarely. Deposits along Bowman capsule can also be found. The light-chain deposits are also typically seen along tubular basement membranes (Figure 18) and can be present in the interstitium proper and along vessel walls. In early cases of light chain deposition disease, when the glomeruli appear essentially unremarkable by light microscopy and fluorescence for monoclonal light chains is inconclusive, lightchain deposits may not be recognizable ultrastructurally. Although in some of these cases, interstitial and vascular deposits may be noted and provide evidence to make or support a definitive diagnosis, in a significant number of cases they are absent in these locations. Ultrastructural immunogold labeling has been proven to be very valuable in

confirming the diagnosis in a variety of settings5,6,12 in a small number of selected cases (Figure 19). In contrast, in diabetic nephropathy the lamina densa of the glomerular basement membranes is classically thickened, and subepithelial lamellation is often also present. No deposits are present along the thickened glomerular basement membranes or in the expanded mesangial areas.

There are well-documented cases in which the immunofluorescence findings are diagnostic of light/heavy chain deposition disease and unequivocal deposits cannot be identified by electron microscopy.9,10 A typical fluorescence pattern (ie, monoclonal linear staining along peripheral capillary walls and/or tubular basement membranes and/or mesangial areas for light or heavy chains) is sufficient to make a definitive diagnosis.

Light and heavy chain deposition disease may be associated with generalized systemic manifestations and deposition of monoclonal light chains in many organs, not only kidneys.12,54,55

AL AND AH AMYLOIDOSIS

Patients with amyloidosis usually present with proteinuria with or without associated nephrotic syndrome. It is typically a disease of individuals in the age range of 50 to 70 years. More than 20 precursor proteins have been found to be amyloidogenic. The clinical setting is variable, depending on the type of amyloidosis.8–11 Regardless of the precursor protein, all types of amyloid appear the same by light and electron microscopies and exhibit identical tinctorial characteristics: Congo red and thioflavins T and S positivity. Amyloidosis, regardless of type, is associated with the amyloid-P component, which can be detected using immunohistochemistry.

The diagnosis of amyloidosis may be difficult in early stages of the disease process because the amount of amyloid deposition may be small and very focal and segmental (Figure 20, A and B). Mesangium and blood vessel walls are the most common early sites of amyloid deposition in the renal parenchyma. Nodular mesangial expansion is seen commonly (Figure 20, C). The normal mesangial matrix is destroyed by activated metalloproteinases,56 and amyloid fibrils replace it (Figure 20, D). Silver stain is helpful in showing expanded mesangial areas that have lost their silver positivity as a result of the replaced mesangial matrix (Figure 20, B). Amyloid is usually weakly periodic acid–Schiff positive (Figure 20, A) and stains blue with the trichrome stain. Congo red stain may not show positivity, or the expected apple green birefringence may be very difficult to demonstrate due to the small quantities of amyloid present. Sections should be cut at 9m to maximize the ability to detect small amounts. Thioflavin T or S stains are more sensitive if small amounts of amyloid are to be detected (Figure 21). A helpful ‘‘trick’’ to identify small amounts of amyloid is to place the Congo red stain under fluorescence light, which will make amyloid deposits (even very small ones) appear bright red (Figure 22). In addition, there may be significant challenges, even after a definitive diagnosis of amyloidosis is made, to establish a connection with monoclonal lightor heavy-chain immunoglobulin components, as discussed later in this article.

Although in most cases light microscopy allows one to make a definitive diagnosis of amyloidosis, detection of early amyloidosis requires a high level of suspicion and a very careful evaluation of the material.5 These cases may be confused with minimal-change glomerulopathy, be-

cause the amyloid deposition can be very focal and segmental, and therefore easy to miss (Figures 20, A, and 21, A). Correlation of light, immunofluorescence, and ultrastructural findings is extremely important to make the correct diagnosis. Because amyloid deposits can be small and subtle and confused with hyalinosis in glomerular and vascular locations, detecting lightor heavy-chain monoclonality by immunofluorescence can be very informative and the triggering event to lead to a more careful evaluation of the light microscopic findings. Ultrastructural confirmation is crucial in some of these cases. Ultrastructural immunoelectron microscopy can label the precursor protein associated with the amyloid fibrils (Figure 20, D).

Amyloid deposition can occur in any of the renal compartments (Figure 23). Although in most cases amyloid deposits are present in all compartments, albeit with variation in quantity, there are a minority of cases in which only one compartment is affected. Tubular casts with material exhibiting fibrillary material with staining and ultrastructural characteristics diagnostic of amyloid can be seen in cases with widespread renal amyloidosis. However, tubular casts containing amyloid as the only manifestation of renal amyloidosis have been reported in rare cases (Figure 24).31

Amyloid is composed of randomly arranged, nonbranching fibrils that measure 8 to 12 nm. Amyloid is first detected in mesangial areas in the glomeruli, and with time the fibrils are also noted to extend into peripheral capillary walls. They can be seen in subepithelial and subendothelial areas (Figure 25, A and B), and in some cases

the fibrils replace the glomerular basement membranes and are seen extending transmurally (Figure 25, C).

Once a diagnosis of amyloidosis is established, staining for the precursor protein allows proper identification of the type.57 Although AL amyloidosis is the most common form of amyloidosis in the United States and the Western hemisphere, fewer than 10 cases of AH amyloidosis have been reported in the literature (Figures 26 and 27).58 Immunofluorescence and histochemical stains are routinely used to evaluate amyloid protein precursors. The routine panel of immunofluorescence stains used in renal biopsies includes antibodies to detect light/heavy chains (Figures 26, B, and 27, B) and fibrinogen, all of which can be amyloid precursor proteins. Commercially available antibodies to light and heavy chains of immunoglobulins may not always detect light and heavy chains because truncated forms of these are generally present in the amyloid tissue deposits. Negative stains for these do not rule out AL or AH amyloidosis.59 Ultrastructural labeling techniques can result in characterizing a subset of amyloid cases that cannot be typed at the light microscopic level with certainty (Figure 28).

The use of antibodies to different subgroups of light chains may help in detecting amyloid deposits, because their chance of detecting abnormal subtype-specific antigenic epitopes is significantly increased. Identifying the wrong type of amyloid may have significant adverse consequences. Rare cases have been reported where more than one type of amyloid is present. The use of tandem mass spectroscopy on formalin-fixed, paraffin-embedded specimens is superior to other techniques and provides

precise characterization by identifying specific protein sequences of the various types of amyloid. Unfortunately, this methodology is still in the hands of research laboratories and not widely available for general diagnostic use.57 At the ultrastructural level, amyloidosis must be distinguished from fibrillary glomerulopathy.59–63 In both conditions, the fibrils are nonbranching and randomly arranged, but in amyloidosis they measure 8 to 12 nm in diameter, whereas in fibrillary glomerulopathy they range from 12 to 25 nm (Figures 28, B, and 29).60–63 Congo red and thioflavins T and S stain amyloid but not the fibrils

in fibrillary glomerulopathy.

A possible source of confusion is that the amyloid-P component is also present in fibrillary glomerulopathy. Other important distinctions are between amyloid fibrils and mesangial matrix accentuation resulting in a fibrillary appearance (Figure 30), and precollagen and collagen fi- bers. Matrix fibrils are approximately 6 nm in diameter. Collagen fibers exhibit their classical periodicity at 65 nm, and precollagen fibers are usually present in a background where typical collagen is also noted.60

Immunotactoid glomerulopathy can also be in the differential diagnosis. In this condition, there is deposition

of microtubular structures which measure 20 to 60 nm in diameter, predominantly in the mesangium. Congo red, thioflavins T and S, and stain for amyloid-P component are all negative in this condition. Interestingly, immunotactoid glomerulopathy is often associated with an underlying plasma cell dyscrasia.62

An unusual morphologic manifestation of amyloidosis that mimics an immune complex–mediated process has been documented in the literature.64 The glomerular capillary walls exhibit a bright red appearance on the he- matoxylin-eosin stain (Figure 31). The unusual deposits in this type of glomerular amylodosis are Congo red positive with apple green birefringence and thioflavin T positive, and are composed of randomly disposed, nonbranching 8- to 12-nm fibrils, fulfilling all criteria for the diagnosis.

Amyloidosis is a systemic disorder, and amyloid deposits may be found in any organ. Pathologists are sometimes asked to examine fat pad aspirates or gingival or rectal biopsies to diagnose systemic amyloidosis. The same criteria for amyloid diagnosis as in the kidney apply in other sites.

Glomerular amyloid formation generally occurs first in the mesangium. Mechanisms involved have been eluci-

dated, and key steps in the process have been delineated.65 One of the most fundamental steps involves the transformation of mesangial cells from their normal smooth muscle into a macrophage phenotype and engaging in avid endocytosis and delivery of the amyloidogenic light chains to the lysosomal compartment, where fibril formation occurs.65

CONCLUSIONS

Renal lesions associated with plasma cell dyscrasias are quite varied in terms of morphologic manifestations. They can occur in any of the renal compartments, and in some cases in more than one compartment. A significant factor associated with the variability of morphologic manifestations arising from the damage to various portions of the nephron emanates from the physicochemical characteristics of the abnormal light and heavy chains present in these patients.37–39,66–70 Glycosylated light chains are 4 times

more amyloidogenic than nonglycosylated ones.67 6 Light chains display a unique tropism for renal amylodosis.70 Host factors,71 including genetic polymorphism, may also be important in explaining the propensity of a particular type of pathologic lesion to develop in a given patient and the diversity of renal lesions that may be encountered in different patients. Other factors may also predispose a given patient to develop a particular type of pathology. For example, patients with plasma cell dyscrasias with certain types (not any kind) of circulating light chains who become dehydrated, hypercalcemic, or are given loop diuretics, such as furosemide, increase significantly their risk of developing light chain cast nephropathy.72 Although our understanding of the pathogenesis and ability to make diagnoses of light-chain– or heavy-chain–associ- ated renal diseases has increased substantially in the last 2 decades, there are still significant challenges that remain. It should also be noted that not all conditions associated

Figure 30. Accentuated mesangial matrix. Transmission electron microscopy. Mesangial matrix with an accentuated fibrillary appearance. Fibrils are thinner (in the range of 6 nm in diameter) than those in amyloidosis (uranyl acetate and lead citrate stain, original magnification 17 500).

Figure 31. Light chain amyloidosis. Peculiar morphologic glomerular expression of light chain amyloidosis with thickened and markedly eosinophilic capillary walls mimicking ‘‘wire-loop’’ lesions (hematoxylineosin, original magnification 500).

with plasma cell dyscrasias have been covered in this review.

This article has focused on highlighting advances that have taken place in the field and pointing out areas where additional work is needed. Now that a molecular understanding of the various morphologic manifestations of these diseases has been achieved by effective translational efforts that have taken data from the research laboratory into the clinical arena, new therapeutic modalities aimed at stopping, ameliorating, or preventing renal damage in these conditions can be developed. The understanding of the pathogenesis of these disorders that has been acquired will lead to the development of sound and rational therapeutic strategies, primarily aimed at molecular targets.

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