Immune-Mediated Glomerulonephritis.Glomerulonephritis (GN) most often results from immune-mediated mechanisms, most notably after the deposition of soluble immune complexes within the glomeruli and less commonly after the formation of antibodies directed against antigens within the GBM. Antibodies to the basement membrane (anti-GBM disease) bind and damage the glomerulus through fixation of complement and resulting leukocyte infiltration. This mechanism of GN has been well documented in human beings and nonhuman primates but only rarely in other domestic animals. To confirm the diagnosis of anti-GBM disease, Ig and complement (C3) must be demonstrated within glomeruli. Antibodies must be eluted from the kidneys and found to bind to normal GBMs of the appropriate species. Immune-complex GN (ICGN) occurs most commonly in dogs and cats and is the most common glomerular disease in dogs, accounting for 48% of glomerular diseases in a recent study. ICGN often occurs in association with persistent infections or other diseases that characteristically have a prolonged antigenemia that enhances the formation of soluble immune complexes. ICGN can be associated with specific chronic viral infections, such as feline leukemia virus (FeLV) or feline immunodeficiency virus (FIV); chronic bacterial infections, such as pyometra or pyoderma; chronic parasitism, such as dirofilariasis; autoimmune diseases, such as canine systemic lupus erythematosus; and neoplasia (Box 11-8 ). In addition to the role of persistent infections, a familial tendency for development of ICGN has been described in a group of related Bernese mountain dogs. Diseases with Immune-Complex Glomerulonephritis
ICGN is initiated by the formation of soluble immune complexes (antigen-antibody complexes) in the presence of antigen-antibody equivalency or slight antigen excess, which then do the following:
Although circulating immune complexes may contribute to this process, antibody binding to endogenous glomerular antigens or entrapped nonspecific antigens is more common. Direct action of C5b to C9 on the glomerular components results in activation of both glomerular epithelial cells and mesangial cells to produce damaging mediators, such as oxidants and proteases. Many specific factors determine the extent of deposition of soluble immune complexes in the glomerular capillary walls. These include persistence of appropriate quantities of immune complexes in the circulation, glomerular permeability, the size and molecular charge of the soluble complexes, and the strength of the bond between the antigen and antibody (avidity). Small or intermediate complexes are the most damaging because large complexes are removed from circulation through phagocytosis by cells of the monocyte-macrophage system in the liver and spleen. An increase in local glomerular vascular permeability is necessary for immune complexes to leave the microcirculation and deposit in the glomerulus. This process is usually facilitated via vasoactive amine release from mast cells, basophils, or platelets (see Fig. 11-27, A). Mast cells or basophils release vasoactive amines because of the interaction of the immune complexes with antigen-specific IgE on the surface of these cells, by stimulation of the mast cells or basophils by cationic proteins released from neutrophils, or by the anaphylatoxin activity of C3a and C5a. Platelet-activating factor (PAF) is released from immune complex–stimulated mast cells, basophils, or macrophages and causes platelets to release vasoactive amines. Localization of the complexes within the various levels of the basement membrane or in subepithelial locations depends on their molecular charge and avidity. Once small, soluble immune complexes are deposited within the capillary wall, they can become greatly enlarged because of interactions of immune complexes with free antibodies, free antigens, complement components, or other immune complexes. After immune-complex deposition, glomerular injury can also occur from the aggregation of platelets and activation of Hageman factor, which results in the formation of fibrin thrombi that produce glomerular ischemia. Furthermore, glomerular epithelial cell and ECM damage can result directly from the terminal membrane attack complex of the activated complement cascade (C5 to C9). This can result in epithelial detachment (causing proteinuria) and GBM thickening subsequent to upregulation of epithelial cell receptors for transforming growth factor (Fig. 11-27, B). Cell-mediated cytotoxic responses (from sensitized T lymphocytes) to glomerular antigens or complexes may exacerbate renal lesions. Complexes themselves may modulate the immune response through interaction with receptors on various cells. Finally, if exposure of the glomerulus to immune complexes is short-lived, as in a transient infection such as infectious canine hepatitis, glomerular immune complexes will be phagocytosed by macrophages or mesangial cells and removed, and the glomerular lesions and clinical signs may resolve. Conversely, continual exposure of glomeruli to soluble immune complexes, such as in persistent viral infections or chronic heartworm disease, can produce progressive glomerular injury, with severe lesions and clinical manifestation of glomerular disease (Box 11-9 ). Progression of Glomerular Immune-Complex Deposition
Ultrastructurally, immune complexes either in the GBM or in a subepithelial location appear as electron-dense granular bodies. Complexes that are poorly soluble, fairly large, or of high avidity often enter the mesangium, where they can be phagocytosed by macrophages and appear ultrastructurally as dense granular deposits within the mesangial stroma or within macrophages. Other ultrastructural changes commonly seen are loss, effacement, or fusion of visceral epithelial cell (podocytes) foot processes, cytoplasmic vacuolation, retraction and detachment of visceral epithelium, and infiltrates of neutrophils and monocytes within the mesangium. A diagnosis of ICGN can be made by immunofluorescent or immunohistochemical demonstration of immunoglobulin and complement components, usually C3, in glomerular tufts. To augment light microscopic findings, transmission electron microscopy can be done to demonstrate typical subepithelial and intramembrane electron-dense deposits, fusion of podocyte foot processes, and intramesangial hypercellularity. In dogs, IgG or IgM are the most common immunoglobulin isotypes demonstrated in ICGN; however, combinations of IgG, IgM, and IgA also occur in the glomeruli of some dogs. In one study, IgA was the only immunoglobulin found in three dogs with ICGN. Both Ig and C3 are usually demonstrated in a granular (“lumpy-bumpy”) pattern using immunofluorescent or immunohistochemical techniques (Fig. 11-28 ; E-Fig. 11-4); however, in anti-GBM disease, as reported in human beings, horses, and a single dog, the antibody deposits have a linear distribution conforming to the basement membranes. It is important to remember that fluorescing deposits indicate the presence of immunoglobulin or complement but do not specifically indicate the presence of disease. In addition, immunofluorescence may be negative when all reactive binding sites are occupied, thus complicating diagnosis of this condition.  Antibody-Mediated Glomerular Injury. A, Normal structure of the glomerulus. Antibody-mediated glomerular injury can result either from the deposition of circulating immune complexes (B) or from formation of complexes in situ (C and D). Using immunofluorescence microscopy (not shown here), antiglomerular basement membrane (anti-GBM) disease (C) and antiglomerular (visceral epithelial cell) disease (D) are characterized by linear patterns of immunofluorescence deposition in glomeruli, whereas deposition of circulating immune complexes in glomeruli is characterized by granular (“lumpy-bumpy”) patterns (see E-Fig. 11-4). (Courtesy Drs. M.A. Breshears and A.W. Confer, Center for Veterinary Health Sciences, Oklahoma State University; and Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) Immune-Complex Glomerulonephritis, Aleutian Mink Disease, Kidney, Glomerulus, Mink. Intraglomerular immunoglobulin deposits demonstrated by immunofluorescence. Note the granular (“lumpy-bumpy”) pattern of fluorescence in this case of Aleutian mink disease. Immunofluorescence microscopy. (Courtesy Dr. S.J. Newman, College of Veterinary Medicine, University of Tennessee.) The diagnosis of preformed ICGN can be confirmed only by demonstrating that the antibodies from the immune complexes, eluted from glomeruli, do not bind to normal glomerular elements and hence represent deposition of preformed circulating complexes. Once this has been done, the ideal situation would be to identify the causative antigen present in the immune complexes. This process is accomplished by eluting antibodies from diseased glomeruli and attempting to identify their specificity for suspected antigens. For example, antibodies eluted from the glomeruli of dogs with GN associated with severe heartworm disease bind to several Dirofilaria immitis antigens, including the body wall of adult worms, parasitic uterine fluid, and microfilaria. In most cases of immune-complex GN, the specific causative antigen usually escapes determination. Demonstration of electron-dense deposits in mesangial, subepithelial, or subendothelial locations by electron microscopy is also supportive of the diagnosis of immune-mediated GN. Gross lesions of acute ICGN are usually subtle. Kidneys are often slightly swollen, have a smooth capsular surface, are of normal color or slightly pale, and have glomeruli that are visible as pinpoint red dots on the cut surface of the cortex (Fig. 11-29 ). The normal glomeruli of horses are usually visible, so this feature of pinpoint red dots for glomeruli cannot be used for diagnosis in that species. If lesions do not resolve but become subacute to chronic, the renal cortex becomes somewhat shrunken and the capsular surface has a generalized fine granularity. On cut surface, the cortex can be thinned and its surface granular, and glomeruli can appear as pinpoint pale gray dots. With time, more severe scarring can develop throughout the cortex (see the section on Renal Fibrosis). Microscopically, ICGN has several histopathologic forms. Although various classifications of GN have been published, the following simple classification is well understood among veterinary pathologists. Lesions in glomeruli may be described as membranous or membranoproliferative (Fig. 11-30 ). Glomerular lesion localization and distribution can be characterized with the following terminology:
Types of Glomerulonephritis (GN). A, Proliferative GN, pig. The lesion is characterized principally by hypercellularity of the glomerulus due to increased numbers of mesangial cells. H&E stain. B, Membranous GN, dog. The lesion is characterized by generalized hyaline thickening of glomerular capillary basement membranes. It can occur in dogs with dirofilariasis. H&E stain. C, Membranoproliferative GN, horse. Membranoproliferative GN has histologic features of both proliferative GN and membranous GN. Abundant periglomerular fibrosis surrounds this hypercellular glomerulus (mesangial cells). Mesangial matrix is prominent in the top-right area of the glomerulus. H&E stain. D, Glomerulosclerosis, dog. Note the hypocellularity, shrinkage, and hyalinization due to an increase in fibrous connective tissue and mesangial matrix and almost complete loss of glomerular capillaries. In glomerulosclerosis (the end stage of chronic GN), glomeruli are essentially nonfunctional. H&E stain. (A and C courtesy Dr. W. Crowell, College of Veterinary Medicine, The University of Georgia; and Noah's Arkive, College of Veterinary Medicine, The University of Georgia. B and D courtesy Dr. S.J. Newman, College of Veterinary Medicine, University of Tennessee.) Most of the lesions in ICGN are diffuse, but within an individual affected glomerulus, lesions can be either global or segmental. In the more chronic form, a variety of glomerular tuft changes will be noted, depending on whether the damage is related to mesangial proliferation, membranous proliferation, or both. Tufts may be enlarged, shrunken, or normal size depending on the amount of mesangial matrix present. Reduction in cellularity, enhancement of the capillary outlines within the tuft, proliferation of the parietal epithelial cells, expansion of Bowman's space by high protein ultrafiltrate, and variable thickening of Bowman's capsule may also be observed. Glomerulosclerosis (see later) is the stage in which there is a reduction in the number of functional glomeruli with replacement by abundant fibrous connective tissue and subsequent obliteration of Bowman's space due to capsular fibrosis. In addition, in protein-losing glomerulopathies, tubules often contain abundant eosinophilic homogeneous proteinaceous material, and the proximal tubular epithelium often have microscopic eosinophilic intracytoplasmic bodies referred to as hyaline droplets, which represent accumulations of intracytoplasmic protein absorbed from the filtrate. Microscopic details of each type of glomerular disease are discussed in the next sections. Membranous Glomerulonephritis.Membranous GN is characterized by diffuse glomerular capillary basement membrane thickening without obvious increased cellularity. These thickenings are often most obvious when capillary loops at the periphery of the tuft are examined. Special stains such as periodic–acid Schiff (PAS) or Masson's trichrome can assist in membrane examination. Membrane thickening occurs because of the presence of subepithelial immunoglobulin deposits, as the predominant change (Fig. 11-31 ; also see Fig. 11-30, B). These deposits are separated by protrusions of GBM matrix that eventually encompass these deposits. After removal of the deposited material, cavities are left in the GBM and later these fill with GBM-like material, which results in sclerotic change within the glomerular tuft. This is characterized by increased deposition of positive material (periodic acid–Schiff [PAS]) and a lesser amount of fibrosis. This variation is the most common form of ICGN in cats. Sites of Immune Complex Deposition in the Glomerular Filtration Barrier in the Major Types Glomerulonephritis (GN). A, Normal structure of the glomerular filtration barrier. B, Membranous glomerulonephritis. Immune complexes are deposited in the basement membrane just beneath the visceral epithelium. C, Membranoproliferative glomerulonephritis (type I). Immune complexes are deposited in the basement membrane just beneath the vascular endothelium and lead to a granular pattern in the basement membrane. D, Membranoproliferative glomerulonephritis (type II). Immune complexes are deposited in the basement membrane and lead to the irregular deposition of electron-dense material within the lamina densa. Although not shown in this schematic diagram, type I and type II membranoproliferative glomerulonephritis commonly have hypertrophy and hyperplasia (proliferation) of glomerular endothelial cells, epithelial cells, and mesangial cells in response to the immune complexes and the biological processes they induce. Leukocytes (acute inflammation) may also be recruited from the microvasculature into the proliferative response. (Courtesy Drs. M.A. Breshears and A.W. Confer, Center for Veterinary Health Sciences, Oklahoma State University; and Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) Membranoproliferative Glomerulonephritis.Membranoproliferative GN (mesangioproliferative, mesangiocapillary) is characterized by hypercellularity following proliferation of glomerular endothelial cells, glomerular epithelial cells, and mesangial cells. Concurrently, there is an influx of neutrophils and other leukocytes involving capillary loops and the mesangium with thickening of the capillary basement membrane and mesangium (see Fig. 11-30, C and Fig. 11-31). Sometimes, the hypercellularity is more obvious than membranous thickening, and those cases have traditionally been called “proliferative” glomerulonephritis. More recent classification schemes no longer recognize the “proliferative” glomerulonephritis type, and those cases should more appropriately be considered variants of membranoproliferative GN. Membranoproliferative GN is the most common morphologic form of ICGN in the dog. With light microscopy, membranoproliferative GN changes are similar across cases; however, differences can be seen with immunofluorescent and electron microscopy. The latter technique has resulted in subcategorization of human being membranoproliferative GN into types I and II (see Fig. 11-31). Type I lesions, which are typical of those found in domestic animals, are characterized by the presence of subendothelial deposits and a granular pattern after deposition of C3 and lesser quantities of IgG, C1q, and C4. Type I disease appears to be secondary to deposition of circulating immune complexes. Type II is far less common in human beings than type I and is also referred to as dense deposit disease because electron-dense material of unknown composition and smaller quantities of C3 form an irregular deposit within the subendothelial space and the lamina densa. Type II disease may be a form of autoimmune disease, but its pathogenesis is not clear. Several other changes in the glomerulus and Bowman's capsule usually accompany the lesions discussed previously. These changes include adhesions between the epithelial cells of the glomerular tuft and Bowman's capsule (synechiae; singular = synechia); hypertrophy and hyperplasia of the parietal epithelium lining Bowman's capsule; deposition of fibrinogen and fibrinous thrombi in glomerular capillaries, secondary to or as a result of the glomerular damage; and dilated renal tubules filled with homogeneous proteinaceous fluid. An increase in mesangial matrix is often also present. If the damage is mild and the cause is removed, glomeruli can heal without obvious or with minimal residual lesions. However, if the lesion is severe and prolonged, subacute to chronic glomerular changes develop. Bowman's capsule can become thickened, hyalinized, and reduplicated. In severe cases, proliferation of parietal epithelium, an influx of monocytes, and deposition of fibrin can occur within Bowman's capsule, resulting in the formation of a semicircular, hypercellular, intraglomerular lesion known as a glomerular crescent. The glomerular crescent can also undergo fibrosis, and if Bowman's capsule ruptures, glomerular fibrosis can become continuous with interstitial fibrosis. Interstitial and periglomerular fibrosis, foci of interstitial lymphocytes, and plasma cells and glomerulosclerosis may be present in chronic GN. Glomerular Amyloidosis.Amyloid, an insoluble fibrillar protein with a β-pleated sheet conformation, is produced after incomplete proteolysis of several soluble amyloidogenic proteins. Amyloid deposits in patients with plasma cell myelomas or other B lymphocyte dyscrasias (called AL amyloidosis) are composed of fragments of the light (λ) chains of immunoglobulins. In domestic animals, spontaneously occurring amyloidosis is usually an example of what is called reactive amyloidosis (AA amyloidosis). This form of the disease is often associated with chronic inflammatory diseases; the amyloid deposits are composed of fragments of a serum acute-phase reactant protein called serum amyloid–A (SAA) protein. Amyloid fibrils from either source are deposited in tissue along with a glycoprotein called amyloid P component. Glomeruli are the most common renal sites for deposition of amyloid in most domestic animal species, although the medullary interstitium is a common site in cats, particularly in Abyssinian breed. Renal amyloidosis commonly occurs in association with other diseases, particularly chronic inflammatory or neoplastic diseases. However, idiopathic renal amyloidosis (i.e., amyloidosis in which an associated disease process is not recognized) is also described in dogs and cats. The underlying pathogenic mechanisms of idiopathic renal amyloidosis are not known. In one study, 23% of dogs that presented with proteinuria had renal amyloidosis. A hereditary predisposition for the development of reactive amyloidosis (AA) has been found in Abyssinian cats and Chinese Shar-Pei dogs. A familial tendency is suspected in Siamese cats, English foxhounds, and beagle dogs. In cattle, renal amyloidosis is nearly always due to chronic systemic infectious disease. Glomerular amyloidosis is responsible for many cases of protein-losing nephropathy in animals that have notable proteinuria and uremia. It can, like ICGN, result in the nephrotic syndrome. Long-standing glomerular amyloidosis results in diminished renal blood flow through the glomeruli and the vasa recta. Such reduced renal vascular perfusion can lead to renal tubular atrophy, degeneration, and diffuse fibrosis and, in severe cases, renal papillary necrosis. Medullary amyloidosis is usually asymptomatic unless it results in papillary necrosis. Kidneys affected with glomerular amyloidosis are often enlarged and pale and have a smooth to finely granular capsular surface (Fig. 11-32 ). Amyloid-laden glomeruli may be visible grossly as fine translucent to tan dots on the capsular surface. Similarly, the cut surface of the cortex can have a finely granular appearance with scattered glistening foci, less than 0.5 mm diameter in the cortex (see Fig. 11-32). Treatment of kidneys with an iodine solution, such as Lugol's iodine, in many cases results in red-brown staining of glomeruli, which become purple when treated with dilute sulfuric acid (Fig. 11-33 ). This technique provides a rapid presumptive diagnosis of renal amyloidosis. Medullary amyloidosis is usually not grossly recognizable. Amyloidosis, Kidney, Dog. Grossly, kidneys affected by amyloid deposition are diffusely tan, waxy (firm), and of normal size or slightly enlarged. Affected glomeruli are not grossly visible in this specimen, unlike in advanced cases of glomerular amyloidosis or chronic GN. In advanced cases of amyloidosis, glomeruli may be visible as pinpoint, glistening, round, cortical foci. In cats and Shar-Pei dogs, amyloid is deposited in the medullary interstitium, not in the glomeruli. There are also multiple foci of medullary crest necrosis (yellowish-green [arrows]). (Courtesy Dr. G.K. Saunders, The Virginia-Maryland Regional College of Veterinary Medicine; and Noah's Arkive, College of Veterinary Medicine, The University of Georgia.) Amyloidosis, Kidney, Transverse Section, Dog. On the cut surface of fresh kidney treated with Lugol's iodine followed by dilute sulfuric acid, glomeruli containing amyloid are visible as multiple dark blue dots in the cortex. Lugol's iodine treatment. (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) Microscopically, glomerular amyloid is deposited in both the mesangium and subendothelial locations. Amyloid is relatively acellular and can accumulate segmentally within glomerular tufts; thus a portion of the normal glomerular architecture is replaced by eosinophilic, homogeneous to slightly fibrillar material (Fig. 11-34, A ). When amyloidosis involves the entire glomerular tuft, the glomerulus is enlarged, capillary lumina become obliterated, and the tuft can appear as a large hypocellular eosinophilic hyaline sphere (Fig. 11-34, B). Amyloid can be present in renal tubular basement membranes, and these membranes appear hyalinized and thickened. In addition, in cases of glomerular amyloid deposition, secondary changes may be present in renal tubules, which are usually markedly dilated, have variably atrophic epithelium, and contain proteinaceous and cellular casts. Amyloid is confirmed microscopically by staining with Congo red stain (Fig. 11-34, C). When viewed with polarized light, amyloid has a green birefringence (Fig. 11-34, D). Loss of Congo red staining after treatment of a section of affected kidney with potassium permanganate suggests amyloid is AA (i.e., of acute-phase reactant protein origin). Amyloidosis, Glomerulus, Kidney, Dog. A, All glomerular tufts (G) are diffusely and notably expanded by amyloid (pale eosinophilic homogeneous deposits), with the result that they are relatively acellular. H&E stain. B, Amyloid, the pale eosinophilic homogeneous hyalinized deposits, expands the mesangium of the glomerulus (arrow). H&E stain. C, Amyloid stains orange with Congo red staining (arrow), a technique used to confirm it. Note the proteinaceous casts in tubular lumina (arrowhead), a consequence of glomerular damage allowing leakage of proteins into the filtrate (protein-losing nephropathy). Congo red stain. D, Congo red–stained amyloid deposits. These deposits have a light-green (often called apple green) birefringence when viewed under polarized light. Polarized light microscopy. (A courtesy Dr. B.C. Ward, College of Veterinary Medicine, Mississippi State University; and Noah's Arkive, College of Veterinary Medicine, The University of Georgia. B courtesy Dr. S.J. Newman, College of Veterinary Medicine, University of Tennessee. C courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee. D courtesy Dr. W. Crowell, College of Veterinary Medicine, The University of Georgia; and Noah's Arkive, College of Veterinary Medicine, The University of Georgia.) Viral Glomerulitis.Glomerulitis, caused by a direct viral insult to the glomerulus, occurs in acute systemic viral diseases, such as acute infectious canine hepatitis (Fig. 11-36 ), equine arteritis virus infection, hog cholera, avian Newcastle disease, and neonatal porcine cytomegalovirus infection. The lesions are mild, usually transient, and result from viral replication in capillary endothelium. Acute viral GN produces the following gross lesions:
Infectious Canine Hepatitis, Kidney, Cortex, Dog. Renal glomerular endothelial cells contain intranuclear inclusion bodies (arrow). H&E stain. (Courtesy Dr. W. Crowell, College of Veterinary Medicine, The University of Georgia; and Noah's Arkive, College of Veterinary Medicine, The University of Georgia.) Viral-induced intranuclear inclusions are present in glomerular capillary endothelium from viremias of infectious canine hepatitis and cytomegalovirus infections. The inclusions of each disease are similar and are usually large, basophilic to magenta, and either fill the nucleus or are separated from the nuclear membrane by a clear halo. In the other diseases (equine arteritis, hog cholera, maedi-visna, porcine circovirus, and avian Newcastle), viral antigens can be demonstrated in endothelium, epithelium, or mesangial cells by immunofluorescence, immunohistochemistry, or polymerase chain reaction (PCR). In cases of viral glomerulitis, lesions include endothelial hypertrophy, hemorrhages, necrosis of endothelium, and a thickened and edematous mesangium. Clinically, animals are systemically ill from the viral infection, but the glomerular signs are specifically those of a transient proteinuria. Page 2PMC full text: Copyright/LicenseRequest permission to reuse Copyright © 2017 Elsevier Inc. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Nonrenal Lesions of Uremia
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