Renal Aplasia, Hypoplasia, and Dysplasia: Renal aplasia (agenesis) is the failure of development of one or both kidneys so that there is no recognizable renal tissue present. In these cases, the ureter may be present or absent. If present, the cranial extremity of the ureter begins as a blind pouch. A familial tendency for renal aplasia has been observed in Doberman pinscher and beagle dogs. Because life can be sustained when more than one-fourth of renal function is maintained, unilateral aplasia is compatible with life, provided that the other kidney is normal. Unilateral aplasia can go unnoticed during life and be recognized at necropsy. Bilateral aplasia is obviously incompatible with life and occurs sporadically.

Renal hypoplasia designates incomplete development of the kidneys in a variety of species so that fewer than normal nephrons are present at birth. Renal hypoplasia has been documented as an inherited disease of purebred or crossbred Large White pigs in New Zealand and described in foals of various breeds, as well as in dogs (Fig. 11-32, A) and cats (Fig. 11-32, B). Hypoplasia can be unilateral (Fig. 11-32, B) or bilateral; it is rare and difficult to diagnose subtle cases at necropsy or microscopically. In cattle and pigs, the number of renal papillae in the hypoplastic kidney can be compared with those in a normal kidney. Hypoplastic kidneys from pigs and foals have a notable reduction in the number of glomeruli. In foals, for example, 5 to 12 glomeruli are present per low-power field in affected kidneys compared with 30 to 35 glomeruli per low-power field in normal adult kidneys. Unless significant renal mass is compromised by this condition, hypoplasia is clinically silent.

Occasionally, some bovine kidneys are found to have reduced numbers of external lobes, but these kidneys are not hypoplastic and are microscopically and functionally normal; the reduction in external lobes merely represents fusion of the lobes. The shrunken, pitted kidneys in young animals, particularly dogs, are often diagnosed as hypoplastic. However, in most of these cases, these small kidneys are due to the following:

Renal dysplasia is an abnormality of altered structural organization resulting from abnormal differentiation and the presence of structures not normally present in nephrogenesis. Cystic renal dysplasia has been described in sheep and is inherited as an autosomal dominant trait. Renal dysplasia occurs infrequently and like renal hypoplasia, must be differentiated from renal fibrosis and progressive juvenile nephropathy. Dysplastic changes can be unilateral or bilateral and can involve much of an affected kidney or occur only as focal lesions. Dysplastic kidneys can be small, misshapen, or both. Microscopically, five primary features of dysplasia are described as follows:

Interstitial fibrosis, renal cysts, and a few enlarged hypercellular glomeruli (compensatory hypertrophy) are changes seen secondarily to the primary dysplastic changes. The number of nephrons, lobules, and calyces are normal. Bilateral renal dysplasia characterized by persistent mesenchyme and atypical tubular development has been described in foals.

Progressive juvenile nephropathy (familial renal disease) of Lhasa Apso, Shih Tzu, golden retriever dogs, and perhaps other canine breeds could be examples of renal dysplasia (Fig. 11-32, C to E). Asynchronous differentiation is often seen and to a lesser extent several other features of dysplasia. However, until these hereditary lesions of dogs are better characterized, it is probably best to retain the diagnostic term of progressive juvenile nephropathy (see the section on Disorders of Dogs).

Ectopic and Fused Kidneys: Ectopic kidneys are misplaced from their normal sublumbar location because of abnormal migration during fetal development. Ectopic kidneys occur most frequently in pigs and dogs and usually involve only one kidney. Ectopic locations often include the pelvic cavity or inguinal position. Although ectopic kidneys are usually structurally and functionally normal, malposition of the ureters predisposes them to obstruction, which results in secondary hydronephrosis. Fused (horseshoe) kidneys result from the fusion of the left and right cranial or left and right caudal poles of the kidneys during nephrogenesis. This fusion results in the appearance of one large kidney with two ureters. The histologic structure and function of the fused kidneys are usually normal.

Renal Cysts: Renal cysts are spherical, thin-walled, variably sized distentions principally of the cortical or medullary renal tubules and are filled with clear, watery fluid. Congenital renal cysts can occur as a primary entity or in cases of renal dysplasia. The pathogenesis of primary renal cysts is not entirely understood. Cysts are likely derived from normal or noncystic segments of the nephron, most commonly the renal tubules, the collecting ducts, and Bowman’s (uriniferous) space. Although genetic mechanisms can be involved in the pathogenesis of renal cysts, experiments with toxic chemicals indicate that genetic predisposition is not a requirement. The following four mechanisms of renal cystic dilation are considered plausible:

These mechanisms are not mutually exclusive, and several mechanisms often work in concert to create renal cysts.

Cysts range in size from barely visible to several centimeters in diameter. Cysts are usually spherical, delineated by a thin fibrous connective tissue wall lined by flattened epithelium, and are filled with clear, watery fluid. The sources of fluid are glomerular filtrate, transepithelial secretions, or both. When viewed from the renal surface, the cyst wall is pale gray, smooth, and translucent. Cysts can arise anywhere along the nephron and be located in either cortex or medulla. Kidneys can have single or multiple cysts. Some cysts cause no alteration in renal function and therefore are considered incidental findings. Such incidental renal cysts are common in pigs and calves and must be differentiated from hydronephrosis. Acquired renal cysts can occur as a result of renal interstitial fibrosis or other renal diseases that cause intratubular obstruction. These cysts are usually small (1 to 2 mm in diameter) and occur primarily in the cortex.

Polycystic Kidneys: Polycystic kidneys have many cysts that involve numerous nephrons. Congenital polycystic kidneys occur sporadically in many species but can be inherited as an autosomal dominant lesion in pigs and lambs and inherited along with cystic biliary disease in Cairn and West Highland white terriers. The lesion, termed polycystic kidney disease (PKD), is inherited as an autosomal dominant trait in families of Persian cats and bull terriers. Although less well characterized in animals than in humans, this autosomal dominant, high penetrance, heritable condition is thought to be related to mutations in one or more genes (PKD-1 and/or PKD-2) and altered function of the related proteins, principally polycystin-1 and polycystin-2. Manifestation of tubular cysts occurs after mutation of both alleles of these genes, the first of which is a germ-line mutation, and the second is somatic. Polycystin-1 is a cell membrane–associated protein with a large extracellular domain. Polycystin-1, the product of PKD-1, is involved in normal cell proliferation and apoptosis pathways. Although the exact mechanisms for cyst formation are not known, polycystin-1 mutations allow cells either to enter a differentiation pathway that results in tubule formation or to become susceptible to apoptosis. PKD-1 regulates tubular morphology throughout life, but the pathologic consequences are defined by developmental status of the organ with those incurred before the end of terminal renal maturation process, resulting in more severe lesions. Additionally, polycystin-1 is known to be important in both cell adhesion and cell signaling because it is an essential component of desmosomes. Loss of polycystin-1 from its basolateral location may alter critical pathways controlling normal tubulogenesis, thus contributing to cyst formation. Similarly, polycystin-2 functions principally as a localized plasma membrane calcium channel. Additionally, reduced levels of renal cyclic adenosine monophosphate (cAMP) are known to inhibit growth of renal cysts in animal models of PKD so there is an energy-dependent process involved in cyst formation. Further study of these mutated proteins will allow us to narrow the mechanistic pathway of the inherited form and potentially extrapolate to the acquired and sporadic congenital cystic lesions documented. A polycystic renal disease with cysts arising from glomeruli has been described in collie puppies. The gross appearance of the cut surface of a polycystic kidney has been described as “Swiss cheese” (Fig. 11-32, F). As cysts enlarge, they compress the adjacent parenchyma. When extensive regions of renal parenchyma are polycystic, renal function can be impaired.

Immune-Mediated 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 humans 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 occurs in association with persistent infections or other diseases that characteristically have a prolonged antigenemia that enhances the formation of soluble immune complexes. In domestic animals, immune-complex GN occurs most commonly in dogs and cats. Immune-complex GN is associated with specific viral infections, such as feline leukemia virus (FeLV) or feline infectious peritonitis (FIP) virus; 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 immune-complex GN has been described in a group of related Bernese mountain dogs.

Immune-complex GN 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. 11-33, A). Mast cells or basophils release vasoactive amines as a result 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 as a result 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. 11-33, 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 (e.g., FeLV infection) and chronic heartworm disease, can produce progressive glomerular injury, with severe lesions and clinical manifestation of glomerular disease (Box 11-9).

Ultrastructurally, immune complexes either in the GBM or in a subepithelial location appear as electron-dense 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 or effacement of visceral epithelial cell foot processes, cytoplasmic vacuolation, retraction and detachment of visceral epithelium, and infiltrates of neutrophils and monocytes within the mesangium.

A diagnosis of immune-mediated GN can be made by immunofluorescent or immunohistochemical demonstration of immunoglobulin and complement components, usually C3, in glomerular tufts. In dogs, IgG or IgM are the most common immunoglobulin isotypes demonstrated in GN; 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 immune-complex GN. Both Ig and C3 are usually demonstrated in a granular (“lumpy-bumpy”) pattern using immunofluorescent or immunohistochemical techniques (Fig. 11-34); however, in anti-GBM disease, as reported in humans and horses, 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. Additionally, immunofluorescence may be negative when all reactive binding sites are occupied, thus complicating diagnosis of this condition.

The diagnosis of preformed immune-complex GN can be confirmed only by demonstrating that the antibodies from the immune complexes, eluted from glomeruli, are not capable of binding 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 immune-complex GN are usually subtle. The kidneys are often slightly swollen, have a smooth capsular surface, are of normal color or pale, and have glomeruli that are visible as pinpoint red dots on the cut surface of the cortex (Fig. 11-35). 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, immune-complex GN 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 proliferative, membranous, or membranoproliferative (Fig. 11-36). Glomerular lesions can be distributed diffusely, when most of the glomeruli are involved; focally, when only a certain proportion of glomeruli are involved; globally, when an entire glomerular tuft is involved; and segmentally, when only a portion of the glomerular tuft is affected. Most of the lesions in immune-complex GN are diffuse, but within an individual affected glomerulus, the 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. There is typically enlargement of the tuft by the presence of abundant mesangial matrix, a 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. Glomerulosclerosis is the stage where there is a reduction in the number of functional glomeruli with replacement by large amounts of fibrous connective tissue and subsequent obliteration of Bowman’s space due to capsular fibrosis.

Additionally, in protein-losing diseases, the proximal tubular cells 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 outlined in the next sections.

Glomerulosclerosis: In chronic GN, severely affected glomeruli shrink and become hyalinized because of an increase in both fibrous connective tissue and mesangial matrix and a loss of glomerular capillaries (Fig. 11-36, D) and additionally there is periglomerular fibrosis. These glomeruli are hypocellular and essentially nonfunctional. This process is referred to as glomerulosclerosis. There is a specific nomenclature for describing the numbers of glomeruli involved and the location of the lesion in the glomerulus. Glomerulosclerosis can be diffuse, involving all glomeruli, or multifocal. In addition, glomerulosclerosis can involve a whole glomerular tuft (global) or only portions of the tuft (segmental), thus appearing as a nodular or segmental hyalinized thickening in affected glomeruli. Because tubules receive their blood supply from the vasa recta, derived from the glomerular efferent arteriole, glomerulosclerosis reduces the blood flow through the vasa recta, thus decreasing oxygen tension in the tubules. The resulting hypoxia is responsible for tubular epithelial cell death via apoptosis and results because of failure to regenerate to columnar cells. The tubules are lined instead by cuboidal or squamous cells, which lack a brush border and the functions of the normal columnar cells. In addition, chronic proteinuria often accompanies glomerulosclerosis and has been reported to promote tubular epithelial cell loss through apoptosis.

Numerous factors are associated with and accelerate glomerulosclerosis. These factors include the following:

These factors have the following effects:

Glomerulosclerosis is not only the end-stage of GN but also can develop in any chronic disease in which severe damage to nephrons or loss of nephron function occurs. Mild multifocal glomerulosclerosis of unknown cause is often an incidental finding in aged animals. Glomerulosclerosis has been reported occasionally in animals with hypertension and diabetes mellitus. In these cases, global or nodular eosinophilic glycoprotein material (hyaline material) is deposited in the glomerular mesangium.

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–associated (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 breeds. 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 a recent 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 immune-complex GN, 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, pale, and increased in consistency, and have a smooth to finely granular capsular surface (Fig. 11-39). Amyloid-laden glomeruli may be visible grossly as fine translucent 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. 11-39). 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. 11-40). This technique provides a rapid presumptive diagnosis of renal amyloidosis. Medullary amyloidosis is usually not grossly recognizable.

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. 11-41, 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. 11-41, B). Amyloid can be present in renal tubular basement membranes, and these membranes appear hyalinized and thickened. Additionally, 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. 11-41, C). When viewed with polarized light, amyloid has a green birefringence (Fig. 11-41, 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).

Acute Suppurative Glomerulitis: Bacterial (Embolic) Nephritis: Embolic nephritis, which can also be referred to as acute suppurative glomerulitis, is the result of a bacteremia in which bacteria lodge in random glomerular capillaries and to a lesser extent in interstitial capillaries and cause the formation of multiple foci of inflammation (microabscesses) throughout the renal cortex. While the glomeruli appear targeted, this is really a manifestation of renal vascular disease. A specific example of embolic GN is Actinobacillosis of foals caused by Actinobacillus equuli, although many emboli may also affect vasculature within the interstitium (Fig. 11-42). These foals usually die within a few days of birth and have small abscesses in many visceral organs, especially the renal cortex. Embolic nephritis also occurs commonly in the bacteremia of pigs infected with Erysipelothrix rhusiopathiae or sheep and goats infected with Corynebacterium pseudotuberculosis. Arcanobacterium pyogenes was the most common isolate (26/31) from cases of embolic nephritis in necropsy cattle. Staphylococcus aureus, Mannheimia haemolytica, and Streptococcus bovis were also represented.

Grossly, multifocal random, raised, tan pinpoint foci are seen subcapsularly and on the cut surface throughout the renal cortex. Microscopically, glomerular capillaries contain numerous bacterial colonies intermixed with necrotic debris and extensive infiltrates of neutrophils that often obliterate the glomerulus. Glomerular or interstitial hemorrhage can occur as well. As with many other inflammatory diseases, if the affected animal survives, the neutrophilic infiltrates either persist as focal residual abscesses or are progressively replaced by increasing numbers of lymphocytes, plasma cells, and macrophages; reactive fibroblasts; and ultimately coalescing scars.

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. 11-43), 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:

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.

Chemical Glomerulonephritis: Although much less common than the immune-mediated forms of GN, chemically induced glomerular disease occurs in a variety of different ways. Chemicals typically induce glomerular injury by any of the following:

Puromycin aminonucleoside, adriamycin, and histamine-receptor antagonists all induce proteinuria through targeted damage to glomerular epithelial cells. The immunosuppressive drug, cyclosporine A, alters renal perfusion and ultimately the glomerular filtration rate by damaging glomerular endothelial cells. Examples of foreign substances capable of producing immune complexes include injectable hyperimmune serum, gold, and d-penicillamine. Procainamide and hydralazine result in production of antinuclear antibodies, and occupational exposure to hydrocarbon solvents can create anti-GBM antibodies. Often, drug-induced lesions lead to irreversible nephron loss and compensatory cellular and functional hypertrophy of other nephrons. The continuing physical loss of nephrons sets up a cycle for an increase in glomerular hypertension and hyperfiltration, which results in glomerulosclerosis, progressive nephron loss, and interstitial fibrosis.

Miscellaneous Glomerular Lesions:

Inherited Abnormalities in Renal Tubular Function: Inherited abnormalities in tubular metabolism, in transport, or in reabsorption of glucose, amino acids, ions, and proteins have been described in dogs. Primary renal glucosuria, an inherited disorder in Norwegian elkhounds and sporadically occurring in other dog breeds, occurs when the capacity of tubular epithelial cells to reabsorb glucose is significantly reduced. Gross and histologic lesions are not seen because this is a functional disorder. Glucosuria most commonly results from diabetes mellitus, acromegaly, or catecholamine release and predisposes dogs to the following:

A hereditary generalized defect in tubular reabsorption similar to the Fanconi syndrome in humans has been described in Basenji dogs. The underlying tubular defect appears to be abnormal membrane structure of the proximal tubular epithelial cell brush borders because of altered lipid content in the cell membrane. Gross lesions are not identifiable in the early stages. Histopathologic changes in the kidneys are initially minimal, consisting of irregularly sized tubular epithelial cells in the convoluted tubules and loops of Henle. With time, dogs with Fanconi syndrome develop progressive renal insufficiency and associated renal fibrosis. Aminoaciduria, glucosuria, proteinuria, increased phosphaturia, metabolic acidosis, and multiple endocrine abnormalities characterize this disease clinically. Transient acquired forms have been noted in association with copper storage hepatopathy.

The excretion of large quantities of cystine in the urine (cystinuria) is a sex-linked inherited tubular dysfunction seen occasionally in purebred and mongrel male dogs. It is important because it predisposes affected dogs to calculus formation and obstruction of the lower urinary tract (see the section on Urolithiasis).

Acute Tubular Necrosis: Acute tubular necrosis, as described in the section on tubular response to injury, can be seen following exposure to any of the following nephrotoxins (Box 11-10):

These nephrotoxins are covered in greater detail in the next section.

Hydronephrosis: Hydronephrosis refers to dilation of the renal pelvis because of obstruction of urine outflow and is principally caused by a slow or intermittent increase in pelvic pressure. Abrupt increases in pressure, such as those associated with inadvertent surgical ligation of a ureter, more commonly result in a decline in filtration rate in the affected kidney and a lesser propensity to develop hydronephrosis.

Obstruction leading to hydronephrosis can occasionally be caused by congenital malformation of the ureter, vesicoureteral junction, or urethra or from congenitally malpositioned kidneys with secondary kinking of the ureter. The more common causes of hydronephrosis are as follows:

Hydronephrosis occurs in all domestic animals. Depending on the location of the obstruction, hydronephrosis can be unilateral (ureteral) or bilateral (both ureters, bladder trigone, or urethra). Unilateral hydronephrosis is caused by obstruction of the ureters anywhere throughout its length or at its entrance into the urinary bladder. Bilateral hydronephrosis can be caused by urethral obstruction, bilateral ureteral obstruction, or extensive urinary bladder lesions centered on the trigone. When hydronephrosis is unilateral, pelvic enlargement of the kidney can become extensive, even cystic, before the lesion is recognized clinically. If the obstructive process causes partial or intermittent blockage, bilateral hydronephrosis can become notable because of continual urine production and pooling of urine in the expanding pelvis. When obstruction is complete and bilateral, death as a result of uremia occurs before pelvic enlargement becomes extensive.

When the increase in intrapelvic pressure is substantial and sustained, the following occur:

Early changes of hydronephrosis include dilation of the pelvis and calyces and blunting of the renal crest and papillae (Fig. 11-50). When pelvic dilation is progressive, the kidney silhouette is enlarged and rounder than normal, and the cortex and medulla are progressively thinned (Fig. 11-51). Interstitial vascular obstruction from compression produces an expanding front of medullary and later cortical ischemia and necrosis. The continued pelvic dilation causes loss of tubules by degeneration and atrophy, followed by condensation of interstitial connective tissue and fibrosis of the renal parenchyma. In its most advanced form, the hydronephrotic kidney is a thin-walled (2- to 3-mm), fluid-filled sac. This sac is lined by flattened transitional epithelium, which is spared during lesion development. Occasionally, a severely hydronephrotic kidney becomes contaminated by bacteria and the thin-walled sac becomes filled with pus instead of urine. This lesion, referred to as pyonephrosis, is likely the result of blood-borne bacteria lodging in a hydronephrotic kidney.

Pyelonephritis: Bacterial infection of the pelvis with extension into the renal tubules and a concomitant interstitial inflammation is referred to as pyelonephritis. Because of differences in pathogenesis, lesion distribution, and microscopic appearance, pyelonephritis is considered a form of tubulointerstitial nephritis.

Although pyelitis refers to inflammation of the renal pelvis, pyelonephritis is inflammation of both the renal pelvis and renal parenchyma and is an excellent example of suppurative tubulointerstitial disease. The condition usually originates as an extension of a bacterial infection affecting the lower urinary tract that ascends the ureters to the kidneys and establishes an infection in the pelvis and inner medulla (Fig. 11-52). Rarely, pyelonephritis can result from descending bacterial infections, wherein bacterial infection of the kidneys occurs via the hematogenous route (i.e., embolic nephritis). In human pathology, the term pyelonephritis is used to include both ascending and descending infections. Ascending infection, however, is by far the most common cause of pyelonephritis in animals.

The pathogenesis of ascending pyelonephritis depends on the abnormal reflux of bacteria-contaminated urine from the lower tract to the renal pelvis and collecting ducts (vesicoureteral reflux). Normally, little vesicoureteral reflux occurs during micturition. Vesicoureteral reflux occurs more readily when pressure is increased within the urinary bladder, as with urethral obstruction. Most recently, this mechanism has been postulated for end-stage pyelonephritis with mild dysplasia seen in young Boxer dogs in Norway. Bacterial infection of the lower urinary tract can enhance vesicoureteral reflux by several other mechanisms as follows:

The urinary tract has a number of protective features in place to help prevent bacterial colonization and these include the following:

Bacteria that colonize the pelvis can readily infect the inner medulla. The medulla is highly susceptible to bacterial infection because of the following:

Thus bacteria can infect and ascend collecting ducts, cause tubular epithelial necrosis and hemorrhage, and incite a notable inflammatory response. Bacterial infection can progressively ascend within tubules and the interstitium until the inflammatory lesions extend from pelvis to capsule. Chronic pyelonephritis may result from infection superimposed on conditions that result in recurrent obstructive disease or reflux (reflux nephropathy). Recurrent infections lead to recurrent bouts of inflammation that result in scarring.

Because most occurrences of pyelonephritis are ascending infections and because females are more susceptible to lower urinary tract infections, pyelonephritis occurs more frequently in females. Escherichia coli, especially uropathogenic strains that produce virulence factors such as α-hemolysin, adhesions, and P fimbria, is one of the most common causes of lower urinary tract disease and pyelonephritis. Proteus sp., Klebsiella sp., Staphylococcus sp., Streptococcus sp., and Pseudomonas aeruginosa are also common causes of lower urinary tract infection and pyelonephritis in all species. Corynebacterium renale, Arcanobacterium pyogenes, and Eubacterium (Corynebacterium) suis are specifically pathogenic for the lower urinary tract of cattle and pigs, respectively, and are common causes of pyelonephritis. Recent or multiple catheterizations may be a predisposing factor.

A gross diagnosis of pyelonephritis is accomplished by recognizing the existence of pelvic inflammation with extension into the renal parenchyma (Fig. 11-53, A). Pyelonephritis can be unilateral, but it is often bilateral and most severe at the renal poles. The pelvic and ureteral mucous membranes can be acutely inflamed, thickened, reddened, roughened, or granular and coated with a thin exudate. The pelvis and ureters can be markedly dilated and have purulent exudate in the lumina (Fig. 11-53, B). The medullary crest (papilla) is often ulcerated and necrotic. Renal involvement is notable by irregular, radially oriented, red or gray streaks involving the medulla extending toward and often reaching the renal surface. Occasionally, inflammation extends through the surface of the kidneys to produce extensive subcapsular inflammation and localized peritonitis.

Microscopically, the most severe acute lesions of pyelonephritis are usually in the inner medulla. The transitional epithelium is usually focally or diffusely necrotic and sloughed. Necrotic debris, fibrin, neutrophils, and bacterial colonies can be adherent to the denuded surface. Medullary tubules are notably dilated, and their lumina contain neutrophils and bacterial colonies. Focally the tubular epithelium is necrotic. An intense neutrophilic infiltrate, present in the renal interstitium, can be accompanied by notable interstitial hemorrhages and edema (Fig. 11-53, C). If obstruction of vasa recta has occurred, coagulative necrosis of the inner medulla (papillary necrosis) can be severe. Similar tubular and interstitial lesions, although less severe, extend radially into the cortical tubules and interstitium. When the lesions become subacute, the severity of the neutrophilic infiltrates diminishes, and lymphocytes, plasma cells, and monocytes infiltrate the interstitium. Chronic lesions have severe fibrosis. If active bacterial infection persists or is untreated, an intense infiltrate of all inflammatory cell types interspersed with tubular necrosis and fibrosis can be seen. All stages of disease progression can occur in a single kidney.

The renal lesions of chronic pyelonephritis, in which an active bacterial infection exists, include most of the elements of acute inflammation described previously and extensive necrosis of the medulla, patchy fibrosis in the outer medulla and cortex, and variable amounts of pelvic inflammatory exudates. Chronic pyelonephritis often produces a grossly visible deformity of the renal parenchyma because of extensive interstitial inflammation and scarring (Fig. 11-54). Fibrosis secondary to the tubulointerstitial inflammation of pyelonephritis follows the pattern of the acute disease (targeting the renal poles), and results in irregularly distributed, patchy scarring that is seen as deeply depressed regions on the renal capsular surface and linear areas extending through both the cortex and medulla to the pelvis. Such lesions often resemble chronic polar infarcts.

Papillary (Medullary Crest) Necrosis: Necrosis of the renal papillae, or their counterpart, the medullary crest, is a response of the inner medulla to ischemia. Papillary necrosis can be a primary or secondary lesion. Papillary necrosis occurs as a primary disease in animals treated with NSAIDs and is analogous to analgesic nephropathy in humans. The primary disease occurs quite frequently in horses treated for prolonged periods with phenylbutazone or flunixin meglumine. It is important in dogs and cats because of accidental ingestion of or treatment with ibuprofen, aspirin, or acetaminophen at excessive dosages. Drugs associated with papillary necrosis are sometimes referred to as papillotoxins. The medullary interstitial cells are the primary targets of papillotoxins. These cells have a key role in synthesis of prostaglandins, antihypertensive factors, and the glycosaminoglycan matrix of the medullary interstitium. Interstitial cell damage decreases prostaglandin synthesis, which reduces normal blood flow and causes ischemia, increases tubular transport, and modifies the interstitial matrix; the net effect is degenerative changes in tubular epithelial cells in the inner medulla. In addition to its inhibition of prostaglandin biosynthesis, acetaminophen also causes direct oxidative damage to medullary tubular epithelium after covalent binding to the cells, further enhancing necrosis of the renal papillae.

Secondary papillary necrosis results from the following:

Reduced blood flow in vasa recta:

Compression of renal papilla by:

The outer medulla and the cells of the thick ascending loop of Henle in particular are the least well perfused of any zones of the kidneys. This is because the medulla has little direct perfusion; instead, most of the medullary blood supply comes from the cortex after passing through the glomeruli and entering the vasa recta. Because of this limited blood flow, in addition to the high metabolic medullary cellular demand, any lesion or disease process that further reduces medullary blood flow can cause ischemic necrosis (infarction) of the papillae. Additionally, the high metabolic demand for cell transport and the maintenance of an ion gradient to enhance urinary concentration makes this area particularly vulnerable. This is most evident after ischemic tubular damage where swollen endothelial and tubular epithelial cells, in conjunction with neutrophil adhesion in small vessels, upset the balance of oxygenation and energy demand by the outer medullary tubular cells. Medullary blood flow is ultimately balanced through levels of vasodilators, such as prostaglandin, nitric oxide, and adenosine, and vasoconstrictors, such as endothelin and angiotensin II.

Typically, acute lesions are irregular, discolored areas of necrotic inner medulla sharply delineated from the surviving medullary tissue (Fig. 11-55). The affected tissue, which initially undergoes coagulation necrosis, is yellow-gray, green, or pink. With time, the necrotic tissue sloughs, resulting in a detached, friable, and discolored tissue fragment in the pelvis. The remaining inner medulla is usually attenuated and on cross-section is narrowed. Overlying cortex can be somewhat shrunken because of atrophy of some of the nephrons caused by blockage of their tubules in the affected medulla. Small pieces of sloughed necrotic medullary tissue pass inconsequentially into the ureter. However, large pieces can obstruct the ureter, causing hydronephrosis, or form a nidus for precipitation of minerals, resulting in the formation of pelvic or ureteral calculi. Papillary necrosis is usually an incidental finding at necropsy and rarely leads to progressive renal damage and failure.

Granulomatous Nephritis: Granulomatous nephritis is an interstitial disease that often accompanies chronic systemic diseases that are characterized by multiple granulomas in various organs. In domestic animals, granulomatous nephritis has been associated with a variety of infectious agents, including viruses (feline coronavirus [see the section on Disorders of Cats], porcine circovirus), bacteria (mycobacteria), fungi (Aspergillus sp.), and parasites (Toxocara sp. and Angiostrongylus vasorum larvae/eggs). Common to each, however, is the formation of grossly visible granulomas randomly scattered throughout the kidneys, especially in the cortex.

Granulomatous nephritis is also caused by a variety of granuloma-inducing infectious agents, including fungi such as Aspergillus sp., Phycomycetes, or Histoplasma capsulatum; algae, such as Prototheca sp.; Rickettsia such as Ehrlichia canis; protozoa such as Encephalitozoon cuniculi; and bacteria such as Mycobacterium bovis. Small, gray-white, granulomatous foci (2 to 5 mm) or larger nodules (up to 10 cm in diameter) can be scattered randomly throughout the kidneys of animals with granulomatous nephritis. These foci are white to tan, dry, and granular and can have calcified, caseous centers. Microscopically, lesions are characterized by central foci of necrosis surrounded by epithelioid macrophages, variable minerals, and giant cells that contain acid-fast bacteria.

In cattle, granulomatous nephritis is part of the multisystemic granulomatous disease caused by hairy vetch (Vicia villosa) toxicosis (see the section on Disorders of Ruminants). Lesions are characterized by multifocal to coalescing cortical granulomas (Fig. 11-56, A). Microscopically, infiltrates of monocytes, lymphocytes, plasma cells, eosinophils, and multinucleated giant cells are seen primarily within the interstitium of the renal cortex (Fig. 11-56, B).

Migratory Toxocara canis larvae can induce small, gray-to-white granulomas (2 to 3 mm) randomly scattered throughout the subcapsular renal cortex of dogs (Fig. 11-57, A). Such lesions probably are due to cell-mediated foreign body immune response to the migrating larvae and are composed of aggregates of macrophages, lymphocytes, and eosinophils surrounded by fibroblasts within concentrically arranged fibrous connective tissue (Fig. 11-57, B). In recently acquired lesions, nematode larvae can often be seen in the center of these lesions (see Fig. 11-57, B). Following death, the larvae become fragmented and the debris is either phagocytosed and eliminated or less commonly retained with a resultant granulomatous response. Lesions heal by fibrosis, leaving a few finely pitted (contracted) foci on the capsular surface.

Xanthogranulomas: Cats with inherited hyperlipoproteinemia have xanthogranulomas in various organs, including the kidneys. We have observed similar renal xanthogranulomas in dogs with hypothyroidism and severe atherosclerosis. These lesions are characterized by foamy, lipid-laden macrophages, lymphocytes, plasma cells, and fibrosis interspersed with cleftlike spaces typical of cholesterol deposits (cholesterol clefts).

Renal Interstitial Amyloidosis: Although glomeruli are the most common renal sites for deposition of amyloid in most domestic animal species, the medullary interstitium is a common site in cats, particularly in Abyssinian breeds. 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. A hereditary predisposition for the development of reactive amyloidosis (AA) has been found in Abyssinian cats and a familial tendency is suspected in Siamese cats. Medullary amyloidosis is usually asymptomatic unless it results in papillary necrosis. Similarly, Shar Pei dogs represent one of the most commonly affected canine breeds to have systemic AA amyloidosis that accumulates preferentially in the renal interstitium, and it is thought to be autosomal recessive in its familial inheritance. The deposition of medullary amyloid may predispose the dog to various aspects of end-stage renal disease, including interstitial fibrosis, lymphoplasmacytic infiltration, tubular atrophy, tubular dilation, mineralization, deposition of oxalate crystals, glomerular atrophy, and glomerulosclerosis.

Epithelial Tumors: Renal adenomas are rare, benign, epithelial neoplasms comprised of proliferations of renal cortical epithelial cells, most often reported in dogs, cats, and horses. They are incidental findings at necropsy and usually appear as a small (1 to 3 cm), white-to-yellow, solitary, well-circumscribed, nonencapsulated mass in the cortex. Microscopically, adenomas are composed of solid sheets, tubules, or papillary proliferations of cuboidal epithelial cells that are uniform in size and have granular eosinophilic cytoplasm and small, round-to-oval nuclei. Mitotic figures, necrosis, and fibrosis are rare. These incidental tumors are clinically asymptomatic.

Oncocytomas are rare benign epithelial tumors that can occur in a variety of tissues. Grossly, renal oncocytomas are tan, homogeneous, well-encapsulated masses composed of oncocytes. Histologically, they are composed of large eosinophilic granular round cells with condensed round nuclei. Ultrastructurally, they are characterized by numerous prominent cytoplasmic mitochondria. Their origin in the kidney is speculated to be from the intercalated cells of the collecting ducts. These tumors are clinically asymptomatic.

Renal carcinomas are the most common primary renal neoplasms and occur most frequently in older dogs. The specific causes of renal adenocarcinomas in humans are well determined compared with those in animal species, but several mechanisms have been proved in natural animal disease or experimental models. These include the following:

These neoplasms are usually large (up to 20 cm in diameter), spherical to oval, and firm. They often are pale yellow and contain dark areas of hemorrhage and necrosis and foci of cystic degeneration. The masses usually occupy and obliterate one pole of the kidney and grow by expansion, compressing the adjacent normal renal tissue (Fig. 11-58, A and B). Histologic types include papillary, tubular, and solid (Fig. 11-58, C), with solid variants being the most poorly differentiated. Metastasis to the lungs, lymph nodes, liver, and adrenal occur frequently. Renal carcinoma has been associated with paraneoplastic conditions, principally polycythemia. This is because of concurrent overexpression of erythropoietin, which increases bone marrow production of red blood cells.

A variant of the typical renal carcinoma has been seen in German shepherd dogs in conjunction with nodular dermatofibrosis. The lesions are hereditary and consist of multifocal, bilateral, renal cystadenomas or cystadenocarcinomas. Grossly, these resemble the adenocarcinomas described previously, but cysts are much more prominent. The neoplastic cells form solid sheets, tubules, or papillary growth patterns, and the cells in the carcinomas are more atypical and anaplastic. Cells vary in shape from cuboidal and columnar to polyhedral, vary in size, and have clear or granular eosinophilic cytoplasm. Nuclei range from small, round, granular, and uniform to large, oval, vesicular, and pleomorphic. Mitotic figures are numerous. These neoplasms have a moderate fibrovascular stroma.

Transitional cell papillomas and transitional cell carcinomas arise in the renal pelvis and lower urinary tract and when large, can obstruct urinary outflow. Such carcinomas can invade into the kidney and typically carry a poor prognosis. The morphologic features of transitional cell neoplasms are discussed later with the urinary bladder neoplasms (see the section on the Lower Urinary System).

Mesenchymal Tumors: Occasionally, fibromas, fibrosarcomas, or hemangiosarcomas originate in the kidneys. Primary renal sarcomas are rare. Microscopically, in hemangiosarcomas (HAS), neoplastic spindle cells are arranged in solid interlacing bundles and whorls or as variable channels lined by neoplastic endothelium. Cellular pleomorphism and mitotic rate are relatively low. Dogs with renal HAS have protracted disease progression with improved 1-year survival rates and longer median survival times compared to dogs with splenic carcinoma or retroperitoneal HAS.

Metastatic Tumors: Carcinomas and sarcomas (metastatic tumors) arising in other organs can metastasize to the kidneys and are characteristically composed of randomly scattered multiple nodules, usually involving both kidneys (Fig. 11-59). Renal lymphosarcoma occurs with some frequency in cattle and cats, particularly as part of generalized or multicentric lymphosarcoma, which is secondary to retrovirus infection. These neoplastic foci appear as single or multiple homogeneous gray-white nodules (Fig. 11-59, B and E) or as diffuse lymphomatous infiltrates that cause uniform enlargement and pale discoloration of the kidney (Fig. 11-59, C). In cats, renal lymphosarcoma must be differentiated histologically from the necrotizing, fibrinous, and granulomatous renal vasculitis of feline infectious peritonitis and less commonly systemic cryptococcosis (Fig. 11-59, E). Microscopically, neoplastic lymphocytes form obliterative sheets of cells within the renal parenchyma, unrelated to the vasculature (Fig. 11-59, F). Neoplastic lymphocytes have distinct cellular borders, moderate amounts of basophilic cytoplasm, and large round vesicular nuclei with variable prominence to the nucleoli. Lymphosarcoma of the kidney can be treated with some success with chemotherapeutics.

Tumors of Embryonal Origin: Nephroblastomas (embryonal nephroma or Wilms tumor) are common renal neoplasms of pigs and chickens, and are usually recognized as incidental findings at slaughter. They occur in cattle and dogs as well, but less frequently. These neoplasms arise from metanephric blastema and thus occur in young animals. It is speculated that neoplasms result from malignant transformation during normal nephrogenesis or from neoplastic transformation of nests of embryonic tissue that persists in the postnatal kidneys. At necropsy, nephroblastomas can be solitary or multiple masses that often reach a great size and in which recognizable renal tissue can be difficult to detect. They usually are soft to rubbery and gray with foci of hemorrhage. On a cut surface, they are often lobulated. Because nephroblastomas arise from primitive pluripotential tissue, histologic features vary but are morphologically similar to the developmental stages of embryonic kidneys. Characteristically, three components, including primitive, loose myxomatous mesenchymal tissue interspersed with primitive tubules lined by elongated, deeply staining cells and structures that resemble primitive glomeruli, are present. Nests of cells resembling the metanephric blastema can be present. Nephroblastomas also have mesenchymal components such as cartilage, bone, skeletal muscle, and adipose tissue. Clinically, these are usually incidental findings, except in dogs, in which they rarely present as spinal dysfunction, the result of spread to the vertebral canal with secondary spinal cord compression.

Aplasia and Hypoplasia: Ureteral aplasia (agenesis) is the lack of formation of a recognizable ureter, and hypoplasia is the presence of a notably small-diameter ureter. Agenesis of the ureters is the result of failure of the ureteral bud to form and may be unilateral or bilateral. Both conditions are rare. If these defects occur alone, then there is disruption of urinary flow from the kidney to the urinary bladder, resulting in obstructive diseases such as hydronephrosis. If these defects occur with concurrent renal aplasia, then they are clinically silent when unilateral and life-threatening when bilateral.

Ectopic Ureters: Ectopic ureters are ureters that may empty into the urethra, vagina, neck of the bladder, ductus deferens, prostate, or other secondary sex glands. The two possible causes are as follows:

Ectopic ureters are more subject to obstruction or infection, and thus they predispose animals to pyelitis and pyelonephritis. Otherwise, histologically these are normal. This condition is found most frequently in dogs and certain breeds, especially the Siberian husky, are at greater risk. Affected animals present clinically with urinary incontinence and consequent urine dribbling.

Patent Urachus: The most common malformation of the urinary bladder is patent urachus (pervious urachus). This lesion develops when the fetal urachus fails to close and therefore forms a direct channel between the bladder’s apex and the umbilicus. Failure of the urachal remnant and the umbilical arteries and vein to involute is frequently observed in cases of “neonatal” omphalitis, in which abscess formation may result in a patent urachus. Patent urachus has also occurred because of congenital urethral obstruction. Increased bladder pressure, because of the obstruction, forces urine out into the urachus. Rupture of the urachus causes uroperitoneum. The condition must be differentiated from perinatal rupture of the bladder. Foals are affected most often and animals with this defect dribble urine from the umbilicus. Diverticula of the bladder may be primary or acquired and secondary to partial obstruction of the outflow of urine or the result of pressure changes exerted during normal contractions. Occasionally, during urachal closure, the mucosa closes but closure of the bladder musculature is incomplete. When this occurs, a bladder diverticulum (outpouching) at the apex of the bladder can develop. Urine stasis can occur in the diverticulum, predisposing the animal to cystitis or urinary calculi.

• Calculus precursor material in urine in quantities sufficient to be precipitated.

• Substances metabolized in an unusual way, as is uric acid in Dalmatian dogs.

• Substances processed abnormally by the kidney (hereditary defects), as with cystine or xanthine.

• Substances are encountered in the diet in abnormally high levels such as the following:

• Abnormally low levels of a substance are encountered in the diet such as the following:

• Urinary pH, in terms of its optimum for solute precipitation (oxalates at acid pH and struvites and carbonates at alkaline pH)

• Reduced water intake, in relation to the degree of urine concentration and mineral supersaturation

• Bacterial infection of the lower urinary tract (struvite calculi in dogs)

• Obstruction

• Structural abnormalities of the lower urinary system

• Foreign bodies (suture, grass awn, catheter, or needle), or a conglomerate of bacterial colonies, exfoliated epithelium, or leukocytes, which can serve as a nidus for precipitation of mineral constituents

• Drugs excreted in the urine, which may act as a nidus for calculus formation (e.g., sulfonamides and tetracyclines)

Acute Cystitis: Inflammation of the urinary bladder (cystitis) is common in domestic animals. Because inflammation of the ureter (ureteritis) or urethra (urethritis) in the absence of cystitis is rare, this discussion concentrates on cystitis. The causes of acute cystitis are varied; however, for all animal species, bacterial infection is the most common cause. Cystitis may be acute or chronic. Normally, the bladder is resistant to infection, and contaminating bacteria are quickly eliminated by the normal flow of normal urine. Predisposition to urinary tract infection (UTI) occurs when there is stagnation of urine because of obstruction, incomplete voiding at micturition, or urothelial trauma. Other risk factors for UTI include catheterization, vaginoscopy, vaginitis, urinary incontinence, or prolonged administration of medications such as antibiotics that induce bacterial resistance. Bacterial cystitis is more common in females because their relatively short urethra provides a shorter barrier to ascending infections than the longer, narrow diameter of the male urethra. The bacterial species most commonly associated with cystitis are uropathogenic Escherichia coli (α-hemolysin–producing strains) in all animal species; Corynebacterium renale in cattle; Actinobaculum suis (Eubacterium suis) in pigs; Enterococcus faecalis in cats; and Klebsiella sp. in horses. In addition, Proteus sp., Streptococcus sp., and Staphylococcus sp. have been isolated from cases of cystitis in several animal species.

Except for the distal urethra, the lower urinary tract is normally free of bacteria. Sterility of the urinary bladder is maintained through normal repeated voiding of urine and because of the antibacterial properties of urine. These antibacterial properties are attributed to the following:

Cystitis occurs when bacteria are able to overcome normal defense mechanisms and adhere to or invade (colonize) the urinary bladder mucosa. Several factors can enhance colonization and predispose animals to cystitis. Colonization is more likely for strains of bacteria that express molecules on their surfaces that enhance adhesion (e.g., the P and type 1 fimbriae of certain strains of Escherichia coli and Actinobaculum suis and the pH-dependent adherence by pili of Corynebacterium renale). Retention of urine as a result of obstruction or neurogenic causes, such as spinal cord diseases, often leads to cystitis.

Trauma to the urinary bladder mucosa as the result of calculi, faulty catheterization, or other causes can cause erosion and hemorrhage and predispose to bacterial invasion of the lamina propria. Hydrolysis of urea by urease-producing bacteria, such as Corynebacterium renale in cattle and Actinobaculum suis in pigs, releases excessive ammonia that can damage the mucosa and result in urine alkalinity. Bacterial growth can be enhanced when glucosuria is present, such as in diabetes mellitus. Compromise of the host immune system as found with infection by the feline immunodeficiency virus (FIV) can increase susceptibility to bacterial cystitis. Other bacterial virulence factors, such as the Escherichia coli hemolysin, enhance pathogenicity and help bacteria overcome antibacterial factors of the urinary bladder and urine.

Once bacteria gain access to the lamina propria, they cause vascular damage and inflammation. Acute cystitis is often grossly described as hemorrhagic, fibrinopurulent, necrotizing, or ulcerative, and these changes are often sequential over time. Vascular damage predisposes to hemorrhage, leakage of fibrin, and if severe, ischemic necrosis of the bladder. This is often accompanied by mucosal ulceration. Neutrophils are present as a component of vascular damage and in any lesion with accompanying bacterial colonization. However, in each case, components of several of these processes are present. The urinary bladder wall often is thickened by edema, an inflammatory cell infiltrate, and is diffusely or focally hemorrhagic. Hemorrhage is most common when obstruction is concurrently present or after direct trauma from catheterization. Urine in such cases is described as cloudy, flocculent, foul smelling, and red-tinged. The mucosa can have foci of erosion or ulceration, patches or sheets of adherent exudate and necrotic debris, or adherent blood clots (Fig. 11-64, A). Corynebacterium urealyticum in dogs and cats and Corynebacterium matruchotii in a horse were implicated in a condition known as encrusted cystitis, in which plaques and accumulation of sediment predominate. Rarely, surgical debridement in addition to appropriate antimicrobial therapy is required.

Microscopically, acute cystitis is characterized by epithelial denudation with bacterial colonies present on the surface. The lamina propria is intensely edematous and has a diffuse neutrophilic infiltrate. Superficial hyperemia and hemorrhage are usually present (Fig. 11-64, B). A mild perivascular leukocytic infiltrate can occur in the tunica muscularis.

Clinically, dysuria, stranguria, and hematuria characterize acute onset of bacterial cystitis. An inflammatory sediment is detected on urinalysis, and bacteria can be grown in pure culture from urine samples.

Viral causes of acute cystitis are relatively rare in veterinary medicine. In cats, a cell-associated herpesvirus has been found in some cases of mild cystitis. Hemorrhagic cystitis sometimes occurs in malignant catarrhal fever in cattle and deer and occasionally is the dominant gross feature in the disease.

Acute cystitis can result from several chemical causes. Active metabolites of cyclophosphamide, a drug used to treat neoplastic and immune-mediated diseases of dogs and cats, can cause a sterile hemorrhagic cystitis. Cantharidin toxicosis in horses results from ingestion of blister beetles (Epicauta spp.) in alfalfa hay, and hemorrhagic and necrotic cystitis develops from cantharidin excreted through the urinary tract. Chronic ingestion of bracken fern (Pteridium aquilinum) by cattle can result in the syndrome of enzootic hematuria, which can be manifested as acute urinary bladder hemorrhage, chronic cystitis, or urinary bladder neoplasia.

Chronic Cystitis: Chronic cystitis presents as several forms based on the pattern and type of inflammatory response noted. These forms include diffuse, follicular, and polypoid variants. Diffuse variants reveal an irregularly reddened and usually thickened mucosa. There is some epithelial desquamation, and the submucosa is heavily infiltrated with mononuclear inflammatory cells; there are few neutrophils. In addition, there is often connective tissue thickening of the submucosa and hypertrophy of the muscularis layer.

Follicular variants reveal disseminated, nodular, submucosal lymphoid proliferations (2 to 4 mm in diameter) so that the mucosa has a cobblestone appearance (follicular cystitis) (Fig. 11-65). This response is particularly common when cystitis is associated with chronic urolithiasis. These white-gray lymphoid foci are often surrounded by a zone of hyperemia. Often, the lesions are a diffusely thickened, hyperplastic mucosa with goblet cell hyperplasia and a chronic lymphoplasmacytic infiltrate and fibrosis in the lamina propria. Hypertrophy of the tunica muscularis can be observed.

Polypoid masses (chronic polypoid cystitis), seen predominantly in female dogs, likely develop from inflammatory and hyperplastic responses secondary to chronic irritation, which most often arises from persistent bacterial urinary tract infection or uroliths. These hyperplastic transitional epithelial responses are called cystitis cystica, cystitis glandularis, and Brunn’s epithelial nests. Inflammation, epithelial proliferation, and development of a nonneoplastic mass occur most typically in the cranioventral bladder wall. The mucosa has single or multiple nodular mucosal masses (Fig. 11-66) composed of fibrous connective tissue and infiltrated with neutrophils and mononuclear leukocytes. The masses are broad-based or pedunculated, ulcerated, or covered by hyperplastic epithelium with goblet cell metaplasia. Chronic polypoid cystitis is characterized by clinical hematuria.

Toxic Cystitis:

Mycotic Cystitis: Mycotic cystitis is occasionally seen in domestic animals when opportunistic fungi, such as Candida albicans or Aspergillus sp., colonize the urinary bladder mucosa. Such fungal infections usually occur secondary to chronic bacterial cystitis, especially when animals are immunosuppressed or subjected to prolonged antibiotic therapy. Occasionally, Blastomyces dermatitidis can produce lower urinary tract lesions in dogs. The urinary bladder is usually ulcerated with proliferation of underlying lamina propria; a generalized thickening of the urinary bladder wall is the result of extensive inflammation consisting of neutrophils, lymphocytes, plasma cells, macrophages and edema, and fibrosis.

• Topical insecticides

• Exposure to marshes sprayed with chemicals for mosquitoes

• Environments with high industrial activity

• Female gender

• Obesity

• Breed (e.g., Scottish terrier)

Epithelial Tumors: Epithelial neoplasms are by far the most common of the urinary system and are classified as transitional cell papillomas, transitional cell carcinomas, squamous cell carcinomas, adenocarcinomas, and undifferentiated carcinomas, as follows:

Metastasis of urinary bladder carcinomas is most often first seen in regional lymph nodes adjacent to the aortic bifurcation, including the deep inguinal, medial iliac, and sacral lymph nodes. Other potential sites of metastasis include lungs and kidneys, with metastasis to other parenchymatous organs occurring later.

Mesenchymal Tumors: Mesenchymal tumors, including fibromas, fibrosarcomas, leiomyomas, leiomyosarcomas, rhabdomyosarcomas, lymphosarcomas, hemangiomas, and hemangiosarcomas, occur in the lower tract. Primary fibrosarcomas, leiomyosarcomas, hemangiomas, and hemangiosarcomas are rare. Mesenchymal tumors are classified as follows:

• Hyperuricemia

• Hyperammonemia

• Hyperuricosuria

• Hyperammonuria

• Aciduria

• Any genetic predisposition

• Conversion of hypoxanthine to xanthine

• Conversion of xanthine to uric acid

• Viruses, including feline cell–associated herpesvirus (a strain of bovine herpesvirus 4), feline syncytia–forming virus, and feline calicivirus

• Bacteria

• Fungi