Large Animal Internal Medicine

EVERSION OF THE BLADDER AND PROLAPSE OF THE BLADDER

DAVID C. Van METRE

Eversion of the bladder is an uncommon event that occurs during or shortly after parturition in cows.¹⁰⁰^-¹⁰⁴ Forceful straining moves the bladder fundus caudally, eventually turning the bladder inside-out. The bladder is then forced out of the urethral orifice. Prolapse of the bladder is also a rare periparturient event in cattle, more frequently associated with dystocia.^100,¹⁰¹ In this condition a full-thickness tear of the vaginal wall occurs during delivery, allowing the bladder (and possibly other viscera) to be displaced from the abdominal cavity into the vagina.

Clinical Findings and Differential Diagnosis

Cows with either eversion or prolapse of the bladder have a smooth, spherical mass within the vagina, usually protruding from the vulva. An affected cow may be alert and ambulatory, but if concurrent hypocalcemia, exhaustion, or peritonitis exists, the cow may be recumbent and depressed. Careful vaginal examination is required to differentiate these two conditions from each other and from vaginal prolapse, vaginal polyps, fat protrusion from a vaginal tear, vaginal neoplasia, fetal membranes, and uterine prolapse. Prevention of straining through epidural anesthesia is essential because expulsive efforts can cause herniation of other viscera through the urethra (bladder eversion) or through the vaginal tear (bladder prolapse).¹⁰⁰ Epidural anesthesia also facilitates cleaning of the area because straining may result in continual fecal contamination of the perineum and vestibule.

EVERSION OF THE BLADDER

The mucosal surface of the bladder is exposed. The ureteral openings may be visible on its dorsal aspect, although these may be occluded and difficult to see if the wall of the bladder is edematous.¹⁰³ Vaginal palpation reveals that the protruding tissue originates from the urethral orifice. With time, constriction of the everted bladder by the narrow urethra may cause venous congestion, edema, thrombosis, and eventual necrosis.¹⁰⁰ Palpation and ultrasonographic examination are required for detection of herniation of other viscera through the urethral orifice and into the interior of the everted bladder. Strangulation of incarcerated bowel may occur.^101,¹⁰² Careful fine-needle aspiration of the interior of the eversion has been used to differentiate eversion from prolapse of the bladder. With bladder eversion, aspiration may yield peritoneal fluid, but laceration of herniated bowel is a concern.¹⁰⁰

PROLAPSE OF THE BLADDER

The serosal surface of the bladder is exposed. Careful palpation of the vagina reveals that the bladder protrudes from a full-thickness tear in the floor or lateral wall of the vagina. Other viscera may be present in the vagina as well. Fine-needle aspiration yields urine from the bladder lumen.

Treatment and Prognosis

EVERSION OF THE BLADDER

Manual reduction of the everted bladder may not be possible if it is edematous or if other viscera have herniated into its interior. The dorsal aspect of the urethra may be incised to widen the route through which the bladder is to be replaced.^100,¹⁰¹ Laparotomy is required for assessment of the viability of herniated bowel, and subtotal cystectomy may be performed if extensive bladder trauma or necrosis has occurred.¹⁰¹ The viability of the involved structures is of primary concern for prognosis. Bladder paralysis and rupture are potential sequelae to ischemic damage that develops during eversion.¹⁰⁰ Cystitis and pyelonephritis may develop as well, and antibiotic therapy is warranted if repair is attempted. Animals with chronic conditions may develop hydroureter, hydronephrosis, and renal failure.¹⁰⁴

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PROLAPSE OF THE BLADDER

A flexible catheter may be passed into the urethra to remove urine from the bladder, thereby confirming the diagnosis and facilitating bladder replacement. After catheterization and removal of urine, the bladder can be replaced into the abdominal cavity and the vaginal tear can be sutured. Severe contamination of the peritoneal cavity may render attempts at treatment unjustified. Antibiotic therapy is indicated for surgical candidates.

PELVIC ENTRAPMENT OF THE BLADDER

DAVID C. Van METRE

In pelvic entrapment of the bladder, the apex and fundus of the bladder are displaced caudodorsally into the pelvic cavity, resulting in impaired urine outflow. In one report the condition was diagnosed in two Holstein cows a few days after parturition had occurred, suggesting a potential role of delivery or postpartum straining in bladder displacement.¹⁰⁵ Entrapment of the bladder in a perineal hernia¹⁰⁶ or within a vaginal prolapse¹⁰⁷ may also occur.

Clinical Findings

Bladder emptying is impaired, and the presence of the bladder in the pelvic inlet induces straining. An affected cow may show tenesmus, pollakiuria, and stranguria. On rectal examination a soft, fluctuant mass may be detected beside the vagina.¹⁰⁵ In calves, radiography has been used to demonstrate the pelvic position of the bladder.¹⁰⁸

Differential Diagnoses

Differential diagnoses include proctitis, vaginitis, retained placenta, bladder paralysis, cystitis, and perivaginal abscess. Needle aspiration of the bladder per vaginum has been used to make a definitive diagnosis,¹⁰⁵ although the danger of uterine puncture should be considered.¹⁰⁷ Ultrasonographic examination can also be useful for definitive diagnosis.¹⁰⁷ Draining the bladder through catheterization or needle aspiration facilitates replacement of the bladder by manipulation per vaginum. However, laparotomy was necessary in one cow to reset the bladder because of the development of fibrinous adhesions between the bladder and vagina.¹⁰⁵ In cases of bladder entrapment within a vaginal prolapse, complete correction of the prolapse usually restores the bladder to its normal position.¹⁰⁵

ENZOOTIC HEMATURIA

DAVID C. Van METRE

Enzootic hematuria is a disease of chronic or intermittent hematuria in cattle and sheep and is associated with chronic ingestion of bracken fern (Pteridium aquilinum)¹⁰⁹^-¹¹⁵ (Fig. 34-21). A different fern species, Cheilanthes sieberi, may induce this disease in Australian cattle.^109,¹¹¹ Hemorrhagic cystitis is the initial consequence of exposure to the toxic compound(s) in the plant. With continued ingestion of bracken fern, cattle develop bladder neoplasms of epithelial, mesenchymal, or mixed origin. Bladder infection with bovine papillomavirus type 2 is involved in carcinogenesis.

Fig. 34-21 Bracken fern (Pteridium aquilinum).

Clinical Findings

In most cases, several animals are affected in a group that is grazing a particular pasture or being fed a particular type or cutting of hay. Protracted, possibly intermittent, hematuria is the first clinical sign detected in most animals.¹⁰⁹ Blood clots may be voided on occasion. Chronic blood loss eventually results in tachycardia, tachypnea, exercise intolerance, pale mucous membranes, and a decline in productivity and body condition. Bladder wall thickening and bladder tumors may be palpated per rectum. Proliferative changes or overt neoplasia of the bladder may cause dysuria, pollakiuria, and rarely, obstruction of the bladder trigone. Occasionally, blood clots may cause urethral obstruction. Depending on the magnitude and duration of bracken fern ingestion, hematuria may last for months to years before severe debilitation or death occurs. Ultrasonographic examination of the urinary bladder of affected animals may reveal bladder thickening and an irregularly shaped bladder wall. In an Indian study, affected cattle showed a bladder wall thickness of 4 to 5 mm (normal, 1 to 2 mm).¹¹⁰

The syndrome of enzootic hematuria is quite different from acute bracken poisoning, which occurs after ingestion of large quantities of bracken fern (approximating the animal’s body weight), usually over 1 to 3 months.^111,¹¹² Acute bracken poisoning manifests as an acute coagulopathy or fulminant septicemic crisis associated with severe bone marrow suppression. Clinical signs include fever, profound weakness, epistaxis, hyphema, dysentery, and petechial hemorrhages of the mucosal surfaces and sclera.¹¹¹ Acute bracken poisoning is further described in Chapter 54.

Clinical Pathology

Severe anemia is often seen on hematologic examination of cattle and sheep with enzootic hematuria. Evidence of a regenerative response may not be present if bone marrow suppression is severe. The platelet, segmented neutrophil, and lymphocyte counts may be reduced.¹¹¹^-¹¹³ Urinalysis reveals hematuria, proteinuria, and variable pyuria.¹⁰⁹

Differential Diagnosis

Examination of serum for evidence of hemolysis and analysis of sediment from a freshly voided urine sample for intact red blood cells allow for differentiation of hematuria from the hemoglobinuria found in hemolytic diseases. Icterus, also characteristic of ruminant hemolytic disorders, is not found in cases of enzootic hematuria. Hematuria may be evident in urinary tract infection, but pyuria and bacteriuria are marked, and anemia, if present, is usually mild. Simultaneous involvement of several animals is uncommon with urinary tract infection but common in enzootic hematuria. Hematuria may be evident in cattle affected by malignant catarrhal fever (MCF). Protracted, severe hematuria is rare in cases of urolithiasis, and anemia is also not expected. Without necropsy, a diagnosis of enzootic hematuria requires documentation of access to bracken fern in animals with characteristic clinical signs and laboratory data.

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Epidemiology

Enzootic hematuria has a wide geographic distribution, with cases reported in North and South America, the United Kingdom, Australia, and several European countries.¹⁰⁹ Bracken fern is found in all areas of the United States except the Great Plains, with most livestock poisonings occurring in the Pacific Northwest and upper Midwest.¹¹² The plant grows best in well-drained, fertile soils and is often localized in open areas of forests.¹¹⁴ Sheep and cattle are poisoned by grazing the plant or consuming contaminated hay.¹¹⁴

Enzootic hematuria is primarily seen in adult sheep and cattle. In field cases, cattle grazing infested pastures develop hematuria by 2 to 3 years of age.^109,¹¹⁵ Feeding adult cattle 1 to 2 kg bracken fern/head/day led to hematuria within 10 to 15 months in one trial.¹⁰⁹ Papillomas of the bladder occur as early as 1 year after bracken feeding begins, with invasive carcinomas arising 2 to 6 years later.^109,¹¹⁵

Pathophysiology

All parts of the plant are toxic to sheep and cattle.^111,¹¹² Several compounds in bracken fern possess irritant, mutagenic, immunosuppressive, or carcinogenic activities.^109,¹¹³ These include ptaquiloside (aquilide A), quercetin, and a-ecdysone.¹¹⁶^-¹¹⁹ The carcinogenic principles are present in the milk of cows grazing bracken fern.^120,¹²¹ Bracken fern compounds may cause recrudescence of latent bovine papillomavirus 2 (BPV-2) infections through immunosuppression. Bladder infection with BPV-2 follows, and mutagenic compounds in bracken fern interact with BPV-2 in the bladder to induce local neoplasia.^109,^113,¹¹⁶ Growth of the resultant neoplastic tissue may be enhanced by further exposure to mutagenic bracken compounds.^109,^113,¹¹⁶ Similarly, BPV-4 and mutagens from bracken fern may act in synergy to induce neoplasia of the mucosa of the upper GI tract.^116,^118,¹¹⁹

In multiple species, cyclooxygenase 2 (COX-2) is overexpressed in epithelial neoplasms, including those of the urinary bladder origin. Certain types of tumors of urinary epithelium may coexpress COX-1 and COX-2. Bladder carcinomas from cows with enzootic hematuria have been shown to express both COX-1 and COX-2 at a high level relative to normal controls, when evaluated by immunohistochemical methods.¹²² The efficacy of COX-2 inhibitor drugs on cancer prevention or treatment in cattle at risk for bladder tumors remains to be investigated.

Immunosuppression results from reduction in circulating neutrophil and lymphocyte counts. Neutropenia appears to be a reversible phenomenon that results from bone marrow suppression. Neutrophil counts may normalize within 1 to 2 weeks of cessation of bracken feeding. Lymphopenia persists during periods of low-level ingestion.¹¹³

Necropsy Findings

Tissue pallor from anemia is often appreciated. The bladder wall is thickened and the mucosa hemorrhagic and ulcerated. Microscopic examination of the bladder wall reveals capillary engorgement, intramural hemorrhage, and metaplasia of the bladder epithelium.¹¹¹ Several types of bladder tumors and mixed-origin neoplasms may be present. Metastasis of epithelial neoplasms to the regional lymph nodes or other organs can occur.¹²³ Pharyngeal, esophageal, or ruminal papillomas may be found as well, and carcinomas may develop in these same locations in cattle exposed to bracken fern over several years.¹¹⁵

Treatment and Prevention

Treatment of enzootic hematuria is limited to reduction or elimination of bracken fern in the diet. Wooded areas that support growth of bracken fern can be fenced off, and forage improvement may help to limit incorporation of the plant into hay. If such measures are not feasible, a program of early culling may help to avoid low productivity from anemia and neoplasia. Hematuria will cease if bracken feeding is discontinued before the onset of tumor formation.

URINARY TRACT INFECTION

David C. VAN Metre

Cystitis, ureteritis, and pyelonephritis in ruminants most often result from ascending urinary tract infection (UTI) with Corynebacterium renale or Escherichia coli.¹²⁴ Less common causative organisms include various coliform species¹²⁵ and other members of the C. renale group.¹²⁶ Renal infection via the hematogenous route (suppurative embolic nephritis) is much less common but may result from bacteremia with such agents as Salmonella species, Actinomyces pyogenes, or in small ruminants, Corynebacterium pseudotuberculosis.¹²⁷

Clinical Signs

Cystitis in cattle is typified by dysuria and pollakiuria, with or without gross hematuria and pyuria. During urination the flow rate is often decreased. An affected cow may tread or swish the tail and retain an arched stance after voiding has ceased. Blood, purulent debris, or crystalline material may occasionally be found on the hairs of the ventral commissure of the vulva. Rectal palpation may reveal a thickened, painful bladder. If UTI is limited to the bladder, an affected cow usually does not show generalized signs of infectious disease (e.g., fever, anorexia, depression).¹²⁴

In contrast, cattle with acute pyelonephritis often have a history of an abrupt reduction in feed intake and milk production. Fever, depression, ruminal stasis, scleral injection, and occasional episodes of mild colic accompany the signs of cystitis previously described.¹²⁴ With bilateral or left-sided pyelonephritis, renal enlargement, pain, and a loss of normal lobulation of the left kidney may be evident on rectal examination. Transabdominal ultrasonographic examination is useful for evaluation of the right kidney, because the right kidney usually cannot be reached during rectal examination unless it is greatly enlarged.¹²⁴ In an adult cow, ultrasound evaluation of the right kidney can be performed using a 3.5-MHz transducer at the twelfth intercostal space. This transducer can also be used to view the left kidney at the dorsocranial aspect of the right paralumbar fossa.¹²⁸ Alternatively, the left kidney can be imaged transrectally with a linear-array transducer. Dilation of renal calyces; echogenic, flocculent material within the renal pelvis; abnormal renal shape; and renal enlargement are ultrasonographic findings suggestive of pyelonephritis. Vaginal palpation is usually necessary to detect ureteritis¹²⁴; the ureters may be enlarged and painful when palpated through the vaginal wall.

The clinical signs of chronic pyelonephritis are relatively vague and inconsistent.¹²⁴ Weight loss or poor growth rate, anorexia, and reduced milk production are common presenting complaints. Posture and behavior during urination may be normal, although affected calves have been noted to dribble urine, thereby developing phosphatic calculi adherent to the vulvar hairs and urine scald of the perineum and hindlegs. Ulcerative vulvovaginitis may be present as well.¹²⁹ Polyuria without gross urine abnormalities may be found in some cases. Diarrhea and pale mucous membranes may also be seen during physical examination. Rectal and vaginal examination findings for chronic pyelonephritis are similar to those of the acute form, although the involved structures may not be painful or enlarged when palpated.

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Urinalysis with chemical reagent strips appears to be a sensitive ancillary test for both acute and chronic pyelonephritis. In a study of 15 cases of bovine pyelonephritis, clinical signs suggestive of urinary tract disease were found in only three cows. However, evidence of hematuria or proteinuria was found through routine reagent strip urinalysis in all 15 cases.¹²⁴ Further examination and testing of the urinary tract confirmed a diagnosis of pyelonephritis.

Differential Diagnosis

Mild colic may result from a variety of GI disorders, but urinalysis findings are normal in these conditions. Enzootic hematuria usually affects multiple animals in a particular locale, and access to bracken fern is usually demonstrable. Although dysuria and hematuria may be evident in enzootic hematuria, anemia is profound, whereas pyuria and bacteriuria are mild or nonexistent. Urolithiasis may induce colic, dysuria, and hematuria. However, urolithiasis is almost exclusively a disease of male ruminants, and UTI is more common in females. Bladder distention is a common finding in urolithiasis but rarely occurs in UTI. Other conditions that may cause dysuria include vaginitis, vulvar trauma, perivaginal abscesses, and pelvic entrapment of the bladder. Careful assessment of the neurologic system is warranted in cases of UTI to determine if the underlying cause is bladder paresis or incomplete voiding.

Clinical Pathology

Neutrophilic leukocytosis and hyperfibrinogenemia are evident on hematologic evaluation of cattle with pyelonephritis. Hyperglobulinemia may develop if the infection is established for several days. Severe, protracted proteinuria may cause hypoalbuminemia, and the resultant low plasma oncotic pressure may contribute to the development of diarrhea in occasional cases. In chronic pyelonephritis, anemia may result from reduced erythropoietin production, chronic inflammatory disease, and blood loss through the urine.¹²⁴

If azotemia is found on serum chemistry analysis, the clinician must consider renal and prerenal causes before formulation of a prognosis. Pyelonephritis with azotemia and isosthenuria would indicate bilateral renal involvement, lowering the chances for successful treatment.¹²⁴

Urinalysis is required for definitive diagnosis of UTI, but careful collection technique is important for valid conclusions to be made. Concurrent metritis, vaginitis, or posthitis may result in contamination of urine with blood, bacteria, and inflammatory cells, particularly if the rate of voiding is slow. A midstream or end-stream catch is likely to provide the most accurate culture results.¹³⁰ Tentative identification of the organism may be obtained through Gram stain of the urine.

Urinary tract infection consistently produces hematuria, proteinuria, and bacteriuria on urinalysis. Quantitative culture of a urine sample allows for confirmation of the diagnosis and identification of the causative organism. Although not present in all cases, leukocyte casts provide definitive evidence of pyelonephritis.¹³¹

Pathophysiology

Factors involved in ascending UTI include the dose and virulence of the bacterial challenge, the presence of urogenital trauma (e.g., from calving injuries) or abnormal vulvar conformation, obstetric manipulation, bladder catheterization, and urine retention (as occurs with bladder paralysis or urethral obstruction). After cystitis is established, alterations in the contractility and thickness of the bladder wall may promote vesicoureteral reflux, spreading infection into one or both ureters.¹³² Hemorrhage, fibrin deposition, and epithelial necrosis may result in intermittent ureteral or renal obstruction, which may be responsible for the episodic signs of colic occasionally seen in affected cows. Once pyelonephritis is established, necrosis of papillary and tubular epithelium leads to accumulation of necrotic debris in the renal pelvis, loss of functional nephron mass, abscess formation, fibrosis, and distortion of renal shape. Renal calculi, particularly struvite uroliths, may occasionally develop in cases of pyelonephritis. Crystal deposition on necrotic debris and the high local pH caused by bacterial urease activity may contribute to calculogenesis.

Corynebacterium renale is a large, pleomorphic, club-shaped bacillus that is aerobic, ureolytic, nonmotile, and gram positive.¹²⁶ Pyelonephritis caused by C. renale has been reported in a sheep¹³² and induced experimentally in goats.¹³³C. renale is adapted to and maintained in the bovine and ovine urinary tract and is unlikely to be maintained in the external environment for prolonged periods.¹²⁶ Subclinical carriers and diseased animals transmit the organism through direct vulvar contact or by splashing urine droplets onto the vulvas of susceptible cows. Iatrogenic transmission through contaminated obstetric instruments or urinary catheters is also possible. Venereal transmission of C. cystitidis¹²⁶ and C. renale^134,¹³⁵ from infected bulls may also occur.

Adherence of C. renale to urinary tract epithelium appears to be mediated by pili¹³⁶ in a pH-dependent manner.¹³⁷ Adherence is enhanced under alkaline conditions and inhibited by acidic conditions. This may explain the clinical improvements reported in infected cattle fed salts that promote urinary acidification.¹³⁴ Through ureolysis and ammonia production, the organism maintains urine alkalinity, thereby facilitating colonization of the epithelial surface. A serum antibody response develops after renal infection is established, but this response is rarely curative¹²⁴ and does not appear to impart resistance to reinfection with C. renale.¹³⁸

Ruminant UTI is also frequently caused by Escherichia coli, a ubiquitous, gram-negative coliform bacterium.¹²⁴ The serotype(s) and virulence factors of E. coli involved in bovine pyelonephritis have not been identified. Clinical evidence suggests that UTI results from fecal contamination of the urogenital tract or loss of normal urinary tract defenses.

Congenital defects such as ectopic ureter occasionally result in UTI, presumably from ascending infection of an abnormally positioned ureter. Impairment of bladder emptying, as might occur with bladder adhesions, urachal remnant infection, or diseases of the spinal cord, may promote ascending UTI. Urethral trauma caused by urolithiasis, breeding injury, urogenital papillomas, or catheterization of the urethra may also be conducive to infection.

Epidemiology

An Israeli study found that the prevalence of pyelonephritis on a per-farm basis varied between 0.3% and 2.7%.¹³⁹ UTI is much more common in female ruminants than in males because of the relatively short urethral length in females¹⁴⁰ and the potential for urinary tract contamination and trauma during parturition. Seventy-three percent of pyelonephritis cases developed within the first 90 days after calving, suggesting that the postpartum period is a critical time for initiation of UTI.¹³⁹ Another study identified reproductive tract abnormalities such as pneumovagina, metritis, and poor perineal conformation in 7 of 15 cows with pyelonephritis.¹²⁴

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In the past, C. renale has been regarded as the most common causative organism for bovine pyelonephritis¹²⁵; however, in recent studies from Israel, E. coli has been the most frequent cause.^129,¹⁴¹ Once C. renale infection exists in a herd, the number of subclinically infected cows increases over time, and the infection becomes difficult to eradicate.¹²⁶ Through increased frequency of contact, overcrowded cattle may experience more rapid transmission of infection.

Necropsy Findings

Hemorrhage, ulceration, and fibrin deposition are evident on the epithelium of the bladder and urethra. With chronic infection, polypoid growths may develop in the bladder mucosa; these masses grossly resemble tumors and must be definitively identified by histopathologic examination.¹²⁵ One or both ureters may be enlarged, with purulent debris occasionally occluding the ureteral lumen. Pyelonephritis cases may show gross renal enlargement in acute to subacute cases (Fig. 34-22). On sagittal sectioning of the kidney, viscous, gray, odorless exudate is found within the renal pelvis and extending into the medulla and cortex.¹²⁶ A Gram stain of the exudate is useful for differentiation of C. renale from E. coli infection. Renal abscesses, with gross distortion of renal size and shape, may be seen in cases of chronic pyelonephritis.

Fig. 34-22 Postmortem specimen of unilateral pyelonephritis and ureteritis in a cow. The affected kidney and ureter are greatly enlarged.

Treatment and Prognosis

Aggressive antibiotic therapy is essential for successful treatment of UTI. Penicillin is the treatment of choice for C. renale infection; recommended dosage regimen includes procaine penicillin G (22,000 to 44,000 IU/kg IM twice daily) or ampicillin trihydrate (11 mg/kg IM twice daily).¹²⁴ For valuable animals, higher serum and urinary concentrations of penicillin may be achieved with IV administration of sodium or potassium penicillin (22,000 to 44,000 IU/kg every 6 hours) or sodium ampicillin (10 to 50 mg/kg every 8 hours). Treatment should be continued for a minimum of 3 weeks. Subcutaneous injection of antimicrobial drugs may be necessary to limit muscle pain and swelling during the course of treatment. Urinalysis and urine culture should be repeated 1 week after treatment is discontinued to ensure complete resolution. After prolonged therapy with these extralabel dosages of antibiotics, residue withdrawal times for meat and milk must be extended appropriately. In addition, induction of diuresis through oral or parenteral fluid therapy may aid in removing necrotic debris and bacteria from the lumen of the urinary tract.

Urinary tract infection with E. coli or other coliforms may also be successfully treated with high doses of penicillin or ampicillin.¹²⁴ Achieving high urinary concentrations of these antibiotics may render them effective against many coliforms, even those that show in vitro resistance to the expected serum concentrations of the antibiotic.¹²⁴ Repeated assessment of appetite, attitude, rectal temperature, and reagent strip urinalysis is recommended for monitoring cows with coliform UTI that are receiving penicillin or ampicillin therapy. If these parameters do not improve after 96 hours of treatment, another antibiotic should be chosen.¹²⁴ Gentamicin (2.2 mg/kg IM twice daily) has been used to successfully treat refractory coliform UTI in a cow, but the nephrotoxicity of the drug and the current prolonged slaughter withdrawal period are important considerations.¹²⁴ Trimethoprim-sulfadiazine (15 mg/kg IV once daily)¹²⁵ and ceftiofur (3 mg/kg IV twice daily)¹⁴² have also been used with success.

The prognosis for UTI in ruminants depends on the duration of infection, the extent of UTI (cystitis alone vs. unilateral or bilateral ureteritis and pyelonephritis), and the remaining renal function. The chances for successful treatment are improved if treatment is initiated early in the course of infection. In recent reports the combined case fatality and cull rate for pyelonephritis in dairy cattle varied between 18%¹²⁴ and 33%¹³⁹ for treated cases; however, antibiotic dose and duration varied greatly between these two studies. Cows with pyelonephritis and marked azotemia (BUN >100 mg/dL) were found to be at much greater risk for culling (odds ratio = 60) than nonazotemic cows with pyelonephritis.¹³⁹

Prevention and Control

Isolation of animals infected with C. renale is recommended to limit spread of the organism, and disinfection of heavily contaminated areas is advised. Aseptic technique during urogenital procedures and disinfection of obstetric and surgical equipment will limit iatrogenic transmission. In herds using natural service, venereal transmission by subclinically infected bulls may be difficult to control over the long term. An artificial insemination or mass treatment program may be required to prevent further losses from UTI.

AMYLOIDOSIS

DAVID C. Van METRE

Amyloidosis in cattle is caused by deposition of insoluble protein fibrils in the kidney, GI tract, liver, and adrenal glands. Renal amyloidosis in cattle is characterized as a sporadic, chronic wasting disease. Amyloid deposition in the kidney disrupts the normal glomerular structure, resulting in a protein-losing nephropathy.

Clinical Signs

The most common clinical signs of amyloidosis include chronic diarrhea, weight loss, and poor productivity in mature animals.^143,¹⁴⁴ Generalized or ventral edema may be present as a result of hypoproteinemia. Alterations in appetite and attitude may be present, although this may be caused by concurrent disease. Enlargement of the left kidney may be palpated during rectal examination. The enlarged kidneys generally are not painful and maintain normal lobular patterns. Urine may develops stable foam after hitting the ground or being collected and shaken in a container, a result of high urine protein concentration.

Clinical Pathology

Cattle with renal amyloidosis consistently develop marked proteinuria and hypolbuminemia.¹⁴³ Serum creatinine and BUN levels may be elevated if renal damage is advanced. In cases of chronic, active inflammatory disease, hyperfibrinogenemia and hyperglobulinemia may occur.^143,¹⁴⁴ Polarized light microscopy and electron microscopy have been used to examine urine sediment for the presence of amyloid protein in urine.¹⁴⁵

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Differential Diagnosis

Amyloidosis must be differentiated from other diseases causing chronic diarrhea, hypoproteinemia, weight loss, and poor productivity. Diseases to consider include Johne’s disease, copper deficiency, salmonellosis, bovine viral diarrhea, GI parasitism, and glomerulonephritis. Other than amyloidosis, glomerulonephritis is the only other differential diagnosis routinely displaying prolonged proteinuria. Renal biopsy can be performed to differentiate glomerulonephritis from amyloidosis in the live animal.

Pathophysiology

Amyloidosis of cattle is classified as the reactive (AA) type,^146,¹⁴⁷ which is frequently associated with chronic inflammatory disease in domestic animals and humans.¹⁴⁸ Concurrent inflammatory disease, such as traumatic reticuloperitonitis, pneumonia, mastitis, and metritis, have been found in some, but not all, cattle with amyloidosis.^143,¹⁴⁴ Serum amyloid A protein (SAA) is synthesized in the liver and is a precursor of amyloid A (AA) fibril in tissues.¹⁴⁹ SAA concentrations increase dramatically in disorders such as trauma, neoplasia, and inflammatory disease. An elevation in SAA is apparently required for an animal to develop active amyloidosis.¹⁴⁸ Elevations in SAA as a result of abnormal catabolism by the reticuloendothelial system may also increase AA fibril formation.^148,¹⁵⁰ AA fibrils are resistant to proteolysis, allowing for their accumulation in tissues over time.¹⁴⁶ Accumulation of amyloid in the glomerulus alters glomerular filtration. A resultant hypoalbuminemia develops, which in turn decreases intravascular oncotic pressure. Diarrhea develops as a result of edema or amyloid deposition in the GI tract.¹⁴⁴ The protein-losing nephropathy and diarrhea result in weight loss. Glomerular filtration rate will be reduced if the glomeruli are obliterated by amyloid deposition. Renal or pulmonary thrombosis may develop as a result of the loss of low—molecular-weight anticoagulants through the compromised kidney.¹⁵¹

Necropsy Findings

Renal enlargement with yellow-tan to white discoloration is frequently present. A waxy quality of the renal parenchyma may be appreciated on cut surface of the kidney.¹⁴³ Generalized edema resulting from hypoalbuminemia may be present. Some animals will have renal or pulmonary thrombosis.¹⁴⁴ Other inflammatory lesions may be found in other sites. Histologic examination of the kidney may reveal amyloid deposition in the glomerulus, interstitium, and tubule lumen. Immunohistochemical tests using antihuman AA monoclonal antibody can be used for specific demonstration of amyloid in bovine kidney specimens.¹⁵¹

Prognosis

Because the lesions of amyloidosis are irreversible, the prognosis for affected cattle is poor. The resilient nature of the amyloid protein results in its persistence in tissues, even if the underlying cause of inflammatory disease is treated successfully. Specific treatment for amyloidosis has not been reported in cattle.

GLOMERULONEPHRITIS

DAVID C. Van METRE

Glomerulonephritis (GN) is a rare clinical disorder of ruminants that may result from deposition of antigen-antibody complexes in the glomerular basement membrane or from binding of antibody to intrinsic or foreign antigens in the glomerulus. Glomerular injury occurs subsequent to targeting of glomerular tissues by the immune system. Nonimmune mechanisms may be involved in certain forms of the disease.

Clinical Signs

Cattle with GN may have a history of weight loss, poor productivity, and chronic diarrhea.^152,¹⁵³ Lethargy and generalized edema may be detected on physical examination. Rectal palpation may reveal a mildly enlarged but nonpainful left kidney.¹⁵³ GN may be clinically occult in cattle persistently infected with bovine viral diarrhea (BVD) virus¹⁵⁴ and in cattle with fascioliasis.¹⁵⁵ GN has been associated with pregnancy toxemia in ewes; affected animals tend to show clinical signs typical of pregnancy toxemia¹⁵⁶ (see Chapter 33).

Mesangiocapillary GN has been described in Finnish Landrace lambs of specific lineage in Scotland and Canada.¹⁵⁷ The disease is heritable, but the exact mode of inheritance remains unknown. Clinical signs of this disease begin within hours after birth to 3 months of age. Affected lambs may be dull, ataxic, and appear blind. Fine muscle tremors, colic, and convulsions may also be seen.

Differential Diagnosis

The differential diagnosis for cattle with GN is similar to that for amyloidosis (see preceding section).

Clinical Pathology

Heavy proteinuria, mild anemia, and hypoalbuminemia have been reported in cattle with GN.^152,¹⁵³ Granular casts, red blood cells, and leukocytes were found in the urine sediment of one affected cow.¹⁵² Azotemia, proteinuria, and ketonuria are found in ewes with GN associated with pregnancy toxemia. Mesangiocapillary GN in Finnish Landrace lambs is characterized by uremia, hypoalbuminemia, proteinuria, hypocalcemia, and hyperphosphatemia.¹⁵⁷

Pathophysiology

In humans, GN may result from a variety of infectious, toxic, or autoimmune disorders, all of which induce eventual immunologic injury to the glomerulus.^152,¹⁵⁸ Antibodies may be directed against host or foreign antigens located in the vascular endothelium, mesangial cells, or basement membrane. In addition, circulating immune complexes may deposit in the glomerulus. The ultimate consequences of antigen-antibody interaction in the glomerulus are activation of complement and chemotaxis of leukocytes, both of which result in direct glomerular injury and increased glomerular permeability.¹⁵⁸

Filtration of plasma albumin through the damaged glomerulus results in chronic albuminuria, eventually leading to reduced plasma oncotic pressure and generalized edema. Passage of antithrombin III through the damaged glomerulus and into the urine may result in a hypercoagulable state.¹⁵⁹

Immunohistochemical data suggest involvement of immune-mediated mechanisms for spontaneous GN in cattle^152,¹⁵³ and sheep,¹⁵⁷ GN associated with persistent BVD infection and fascioliasis in cattle,^154,¹⁵⁵ and mesangiocapillary GN of Finnish Landrace lambs.¹⁵⁷ In the last condition a heritable deficiency of the third component of complement has been documented, but the role of this deficiency in GN remains unclear.¹⁵⁶ Glomerulonephritis may also be an incidental histologic finding in animals with acute septic disease.¹⁵⁷

The clinical and histopathologic characteristics of GN of pregnancy toxemia in ewes resemble those of the preeclampsia syndrome of women.¹⁵⁶ Enlarged glomeruli with reduced blood content in glomerular capillaries are found throughout the renal cortex of affected ewes. The renal lesion in preeclampsic women may result from endothelial injury during disseminated intravascular coagulation (DIC) or an excessive glomerular vasomotor response to angiotensin.¹⁶⁰ The lesion can be reversible in women, but the consequences of this condition in ewes have not been described.

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Treatment and Prognosis

Treatment of GN in ruminants has not been described. Because most cases of GN are advanced at diagnosis, the prognosis is poor. Mesangiocapillary GN in Finnish Landrace sheep is not invariably lethal, and some affected lambs may survive until adulthood.¹⁵⁶

HEMOLYTIC UREMIC SYNDROME

DAVID G. RENTER

Hemolytic uremic syndrome (HUS) is classified within the group of thrombotic microangiopathy syndromes.¹⁶¹ HUS is a set of symptoms characterized clinically by acquired, nonimmune hemolytic anemia, thrombocytopenia, and acute renal failure (ARF).¹⁶² Histologically, HUS is characterized by renal thrombotic microangiopathy.¹⁶³ HUS is the most common cause of ARF in young children and infants, with prodromal diarrhea occurring in approximately 90% of cases.¹⁶⁴ Evidence indicates that almost all the postdiarrheal human cases of HUS are caused by enterohemorrhagic (EHEC) or verotoxigenic Escherichia coli infections, and that the majority of the cases in the United States are caused by the EHEC serotype O157:H7.¹⁶⁴ Although three horses^165,¹⁶⁶ and a heifer¹⁶⁷ have been reported with clinical syndromes similar to HUS, an etiologic agent was not identified in any of these four animals.

Clinical Findings

Horses with clinical signs indicative of HUS have exhibited fever, diarrhea, hematuria, hemoglobinuria, profound azotemia, oliguria, and ventral edema.^165,¹⁶⁶ Hematologic findings included leukocytosis, anemia, and evidence of hemolysis.^165,¹⁶⁶ The blood smear of one horse revealed the presence of poikilocytes and schistocytes.¹⁶⁶ All three horses were euthanized after unsuccessful treatment of anuria and azotemia with fluid therapy and diuretics. The reported case in a heifer was fatal postparturient HUS demonstrated by severe progressive anuric renal failure, acute hemolytic anemia, and consumptive thrombocytopenia.¹⁶⁷

In humans, HUS presents as pallor, oligoanuria, edema, seizures (rarely), or generalized hemorrhagic diathesis. In prodromal human cases, this syndrome develops on average 1 week after onset of diarrhea.¹⁶² The classical clinical syndrome of HUS in people includes ARF, hemolysis, thrombocytopenia, and manifestations of DIC.¹⁶³ For treatment of HUS in humans, evidence is insufficient to support use of specific therapies, and some treatments, such as certain antibiotics and motility-modifying agents, may be detrimental.¹⁶² Supportive therapy, including fluid/plasma therapy and dialysis, can be of paramount importance.

Pathophysiology and Necropsy Findings

In humans, HUS is the most common life-threatening complication of hemorrhagic colitis (HC) from EHEC infection. The EHEC strains produce the exotoxins Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2), also referred to as verotoxin 1 and verotoxin 2.¹⁶⁸ Although E. coli O157:H7 is the most widely publicized, as many as 100 different serotypes of E. coli (as well as Shigella and other Enterobacteriaceae) can carry the genes for Stx1 or Stx2 and are capable of causing disease.¹⁶¹

The EHEC organisms, including serotype O157:H7, are noninvasive but attach to the intestinal mucosa and produce characteristic histologic attaching and effacing lesions. The Shiga toxins (Stxs) released from the bacteria are believed to translocate across the mucosa, where they access the systemic circulation. The Stxs bind to specific glycolipid receptors on the surface of vascular endothelial cells, are internalized by endocytosis, and induce cell death through inhibition of protein synthesis.¹⁶¹ Activation of the coagulation cascade after exposure of subendothelial collagen may result in thrombosis of small vessels in the kidney and other organs. Oliguric or anuric ARF can result from fibrin/platelet thrombi in renal vessels and glomeruli, fibrinoid necrosis of vessel walls, congestion of glomeruli, and tubular ischemia. Because the coagulation events may be localized to certain organs, the results of laboratory tests of coagulation (e.g., PT, PTT) are not consistently abnormal.¹⁶⁹

Cattle feces are considered to be the major source of EHEC; however, these bacteria have been isolated from the feces of many other asymptomatic species, including humans. EHEC organisms do not generally cause illness in cattle, although they do colonize the bowel. Fecal contamination of ground beef, other food sources, and water is thought to be the primary mode of transmission of the organisms. However, the small infectious dose makes person-to-person transmission a significant problem, especially in day care, nursing home, and outbreak situations.¹⁶¹

In the four large animals reported with HUS, the inciting cause was uncertain, and the isolation of EHEC or other Stx-producing organisms was not attempted.¹⁶⁵^-¹⁶⁷ The heifer had a necrotizing endometritis, but during postmortem examination of the three horses, no focus of infection was identified. Renomegaly, renal infarcts, and scattered petechial and ecchymotic hemorrhages within the renal parenchyma were apparent on gross necropsy. Acute tubular necrosis and fibrin thrombi within the glomerular capillaries were evident on histologic examination.

Although the etiology was not determined, the clinical signs and pathologic lesions reported in the four large animal cases are compatible with a diagnosis of HUS. Based on these reports, the pathogenesis of HUS in large animal animals shares some features of the disease in humans.

TUBULAR NECROSIS

DAVID C. Van METRE

Tubular necrosis (TN), or tubular nephrosis, is the disease condition that results from a variety of toxic, infectious, or hemodynamic insults to the kidneys. Compounds identified as nephrotoxins for ruminants are listed in Box 34-2. Hemodynamic causes of TN include diseases that reduce renal perfusion (blood loss, endotoxic shock) or that occlude the renal vasculature (DIC, renal vein thrombosis). Bilateral bacterial infection of the kidneys may result in ARF or chronic renal failure (CRF) as a result of destruction of nephrons by bacterial toxins and the host inflammatory response. Renal infection may be established by ascending UTI or by hematogenous infection of the kidneys. Depending on the nature and duration of the primary insult, widespread dysfunction or necrosis of tubular epithelial cells may produce reversible renal injury, ARF, or CRF.

Nephrotoxin	Clinical Findings*
Aminoglycosides	Usually nonoliguric, ototoxicosis possible; hematuria, glucosuria, proteinuria, increased serum trough concentration of drug
Tetracycline	Hematuria, glucosuria, proteinuria; possible hepatocellular enzyme elevation
Ionophores	Diarrhea, dark urine, dyspnea, cardiac dysrhythmias; elevated CK, AST, and indirect bilirubin
Ethylene glycol	Anuria or oliguria, tachypnea, ataxia, weakness; hemolysis, increased anion gap, increased serum osmolality, increased osmolar gap, acidosis, calcium oxalate crystalluria
Oxalate-containing plants, vitamin C	Hindlimb ataxia or paresis, apprehension, salivation; hypocalcemia, calcium oxalate crystalluria, aciduria, increased renal cortical echogenicity on ultrasonogram
Oak, acorns	Hemorrhagic diarrhea, ascites, hydrothorax, subcutaneous and perirenal edema; hyperfibrinogenemia, increased hepatic enzymes
Myoglobin	Muscle stiffness and weakness, dark urine; elevated serum CK and AST, positive reactions for blood and protein on urine chemistry strip, hemolyzed serum not present
Hemoglobin/methemoglobin	Icteric to pale mucous membranes, tachycardia, tachypnea, red or brown urine; positive blood and protein reactions on urine chemistry strip, anemia, elevated serum total protein, hemolyzed serum (hemoglobin only)
Arsenic	Colic, hemorrhagic diarrhea, ataxia; elevated blood and liver arsenic levels

LEPTOSPIROSIS

ROBERT J. CALLAN

Leptospirosis is a complex disease of both animals and humans caused by pathogenic species of Leptospira.¹⁸³^-¹⁸⁹ Pathogenic Leptospira species persist as chronic infections of the renal tubules of the maintenance host species, often causing little or no disease. Transmission to incidental hosts results from direct contact with urine from an infected maintenance host or through environmental and feed contamination with infected urine. Infection in the incidental host can cause acute disease in multiple organ systems, including the kidney, liver, and CNS, as well as result in abortion or reproductive failure. This discussion focuses on Leptospira infection and disease of the renal system of ruminants.

Leptospira is a diverse genus of motile, gram-negative, obligate aerobic, tightly coiled spirochetes approximately 0.1 to 0.3 μm in diameter and 6 to 20 μm in length.¹⁸³^-¹⁸⁵ The bacteria can survive in the environment for up to 6 months.^183,^184,¹⁹⁰ Leptospira species prefer a warm, moist environment with a pH of 7.2 to 8.0. Survival is short under dry conditions or at temperatures below 10°C.¹⁸³ Leptospira does not survive freezing in the envrironment.¹⁹¹

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Before 1989, Leptospira was divided into the pathogenic species, L. interrogans, and the nonpathogenic saprophytic species, L. biflexa. The current taxonomy and classification of Leptospira use a complex system of both serologic and genetic characteristics.^184,¹⁸⁵ Serologic classification is based on antigenic grouping of the lipopolysaccharide (LPS) and other outer surface antigens using the cross-agglutinin adsorption test (CAAT). More than 240 serovars are characterized. Antigenically related serovars are combined into larger serogroups, and serovars may also be further characterized into serotypes. Seventeen genomospecies have been identified based on DNA sequence heterogeneity.^184,¹⁸⁵

Epidemiology

Leptospirosis is predominantly observed under conditions where livestock come in direct or indirect contact with urine from an infected maintenance host (Table 34-3).¹⁸³^-¹⁸⁵ ¹⁹⁰ The prevalence of infection within a maintenance host population tends to be high (30% to 50%); in such populations, infection is often spread between animals by direct contact.¹⁸³ Transmission to incidental hosts is generally by contact with the environment, feed, or water that is contaminated with urine from an infected maintenance host. Transmission can also occur from contact with an infected fetus or uterine discharge. Survival of the bacteria in the environment and the incidence of infection in animals are increased in regions with warm, humid climatic conditions. The seasonal incidence is higher during the summer or fall in temperate regions and during the rainy season in warm-climate regions.¹⁸⁴ Environmental conditions that contribute to moist surroundings and foot abrasions may contribute to Leptospira transmission, particularly in housed dairy cattle.

Table 34-3 Current Nomenclature, Maintenance Host, and Incidental Hosts for Common Leptospira Isolates in Ruminants

Cattle are the primary maintenance host reservoir of L. interrogans serovar hardjo (type hardjopragitno) and L. borgpetersenii serovar hardjo (type hardjo-bovis). L. interrogans serovar hardjo (type hardjopragitno) is isolated primarily from cattle in the United Kingdom, and L. borgpetersenii serovar hardjo (type hardjo-bovis) is observed worldwide. Cattle can also serve as maintenance or incidental hosts for L. interrogans serovar pomona and L. interrogans serovar grippotyphosa.

Serovars hardjo, pomona, and grippotyphosa are most often implicated in renal infection of cattle.¹⁹² Although data are scarce, renal disease caused by leptospirosis in small ruminants appears to be uncommon.^191,¹⁹³ Sheep may serve as subclinical carriers of serovar hardjo.^187,¹⁹⁴ Some serovars of Leptospira have zoonotic potential, and humans are always considered an incidental host.¹⁸³^-¹⁸⁵ ¹⁸⁸

An abattoir study of more than 5000 cattle in the United States identified approximately 2% renal carriers of L. interrogans.¹⁹² Serovar hardjo was the most common renal isolate, followed by serovar pomona and serovar grippotyphosa. A study of Texas slaughterhouse cattle detected Leptospira species in 36% of urine samples by PCR. The seroprevalence for serovars pomona and hardjo was 22% and 15%, respectively.¹⁹⁵ A national survey showed 49% seroprevalence for L. interrogans serovars in cattle, with the highest seroprevalence found in cattle from southeastern, south-central, and Pacific Coast states.¹⁹⁶ Because contact with urine from infected animals is a means of transmission within cattle populations, high stocking density or confinement may increase the rate of infection in a herd.

In general, infection of cattle with the host-adapted serovar hardjo rarely results in acute, severe disease. If present, signs of disease are usually mild in acutely infected cattle and may simply present as cases of undifferentiated fever. Persistent, latent urogenital infection usually follows acute infection, with most overt losses attributable to adverse effects on reproduction.^188,¹⁹⁷^-¹⁹⁹

Acute, severe renal disease is more characteristic of incidental (also termed “accidental”) infection of cattle, particularly calves, with a non—host-adapted serovar of Leptospira. However, exceptions to this generalization do occur because host immunity and virulence of the organism are variable.^187,¹⁸⁸

Clinical Findings

Serovar hardjo is host-adapted to cattle, and many infections are asymptomatic or result in nonspecific reproductive failure or abortion. Leptospira serovar hardjo infection of cattle may produce chronic interstitial nephritis of variable severity, but overt renal dysfunction is rarely observed.²⁰⁰ Chronic infection of the genital tract of cows and bulls is common.^189,²⁰¹ Protracted shedding of the organism in the urine often results, possibly lasting for the life of the animal.^200,²⁰¹ Infertility, stillbirth, abortion, and birth of weak calves are typical clinical manifestations of infection with serovar hardjo in cows.^189,^198,^202,²⁰³ The fetus can be infected in utero, and if it survives the acute infection, it may be born persistently infected.¹⁸³ Fever, agalactia, and mastitis may occasionally occur, and the resulting syndrome has been termed the “milk-drop syndrome”¹⁸⁷ or “flabby udder.”¹⁸⁸ The udder is uniformly soft, and the milk may be yellow- or red-tinged and thick.

In contrast, infection with the non—host-adapted serovars can result in severe systemic disease, hemolytic anemia, hepatitis, interstitial nephritis, and tubular nephrosis in calves and less often in adult cattle.^189,²⁰⁰ Meningitis is a rare manifestation.¹⁹³ Agalactia and mastitis often occur in lactating cows, and pregnant cows may abort. Urine shedding of non—host-adapted serovars by infected cattle can persist for weeks to months.^188,^189,²⁰³ Renal lesions result from direct damage to the vascular endothelium during leptospiremia, hypoxia from endothelial damage and hemolysis, tubular epithelial damage from hemoglobin, and interstitial nephritis.^183,^184,²⁰⁰ Some Leptospira serovars, particularly pomona, produce hemolysins that can cause acute intravascular hemolysis and anemia in cattle.

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Clinical signs associated with acute infection may include fever, anorexia, lethargy, decreased milk production, petechiation, hemolytic anemia, and hemoglobinuria. Oliguria may be seen with interstitial nephritis or hemoglobinuric nephrosis. Elevated creatinine caused by pre-renal or renal causes may be observed on serum chemistry analysis. Examination of the urine may show proteinuria, pyuria, and cellular or granular casts in cases of nephritis. Hemoglobinemia and hemoglobinuria may be observed in patients with leptospire-induced hemolysis and can occasionally result in hemoglobinuric nephrosis.

Pathophysiology

Contaminated feed and surface water, wildlife, rodents, and domestic animals are potential sources of pathogenic serovars for cattle.^183,^184,^187,¹⁸⁸ Leptospires penetrate external mucosal surfaces and scarified or macerated skin. The bacteria multiply locally during an incubation period that can last 2 to 20 days.^183,¹⁸⁴ After the incubation phase, the organism enters the bloodstream through the lymphatics or by direct penetration into the blood vessel. Leptospiremia results in dissemination throughout the body and infection of multiple organs. This bacteremic phase lasts 4 to 7 days. Fever and other systemic signs are often present in clinically affected animals. Humoral antibodies can be detected at the end of the bacteremic phase. Opsonizing antibodies are generated and aid in clearing infection from most tissues in the host.

During the convalescent phase, leptospires may become localized in the mammary gland, kidney, or genital tract, where they appear to be protected from the immune response.^183,²⁰⁴ Depending on the virulence of the serovar involved, chronic renal infection may create few histologic changes, mild interstitial nephritis, or diffuse, severe, lymphocytic interstitial nephritis with fibrosis.¹⁹³ Nephritis may persist long after the host immune response has cleared the organism. Chronic infection of the kidney or reproductive tract allows for transmission of the organism in urine, uterine and vaginal secretions, placenta, fetal tissues, and semen.^187,^189,^201,²⁰⁵ Shedding in the urine may last for weeks to months with non—host-adapted infections. Renal shedding of host-adapted serovars can persist for months to years. The bacteria reside in the lumen of the renal proximal tubules, where they are protected from phagocytes and humoral antibodies. The bacteria do not stimulate a systemic immune response while localized in the proximal tubule lumen, and thus serum antibody titers can decline and become negative even though the kidney is infected and shedding bacteria.

Multiple potential virulence factors may contribute to leptospirosis.^184,¹⁸⁵ Leptospiral LPS and outer membrane proteins are believed to contribute to the development of interstitial nephritis. However, leptospiral LPS has different biochemical properties that make it less toxic than other gram-negative lipopolysaccharides. Motility is an important pathogenic mechanism and contributes to invasion and dissemination of the bacteria. As many as 50 genes are related to leptospiral motility.¹⁸⁵ Pathogenic Leptospira strains produce chemotaxis proteins, and some strains exhibit chemotaxis toward hemoglobin. Adherence to cells is in part conferred by fibronectin-binding protein present on the surface of pathogenic strains but not on nonpathogenic strains. Leptospiral immunoglobulin-like protein A (LigA) may also be involved in attachment and invasion. Additional proteins that may contribute to virulence include hemolysins, sphingomyelinase C, sphingomyelinase H, and hemolysis-associated protein 1 (HAP-1).^184,¹⁸⁵

Diagnosis

The microscopic agglutination test (MAT) is the most widely used serologic test for the diagnosis of leptospirosis in cattle. The MAT detects antibodies to specific serovars, but cross-reactivity occurs between related serovars, particularly within the same serogroup. Thus, an infection with one strain may result in increased MAT titer to multiple serovars. Serum antibody enzyme-linked immunosorbent assay (ELISA) tests have been developed for research but have not yet been adopted in the routine clinical diagnostic setting for animals.²⁰⁶^-²⁰⁹

An elevated serum antibody titer is observed after the bacteremic phase and is suggestive of Leptospira infection when associated with concurrent clinical signs. However, interpretation of a single titer is problematic in vaccinated animals or when endemic exposure is suspected.^189,²⁰⁴ A fourfold increase in MAT titer between acute and convalescent serum samples, or conversion from a negative titer to a titer of 1/100 or greater, supports a diagnosis for both host-adapted and non—host-adapted serovars. However, vaccinated animals may have a diminished serologic response after challenge and renal colonization with L. borgpetersenii serovar hardjo.²¹⁰ Serologic detection of persistent infection with serovar hardjo can be difficult because paired serum titers may be increasing, static, decreasing, or undetectable at examination (e.g., at abortion).^189,²⁰⁴ It is generally recommended to consider the serovar with the highest titer as being the infecting strain. However, recent studies demonstrate that serologic antibody titers may not accurately predict the infecting strain in humans because of cross-reaction between different serovars within the same serogroup.²¹¹ Consultation with a clinical immunologist affiliated with the laboratory performing the MAT is recommended for accurate interpretation of results.

Leptospira shedding in urine and semen can be detected by multiple tests, including urine culture, phase-contrast microscopy, darkfield microscopy, fluorescent antibody (FA), polymerase chain reaction (PCR), nucleic acid hybridization, and immunoblot.^192,^204,^205,²¹²^-²¹⁴ Urine cultures are often unrewarding because of the fastidious nature of the organism, and conclusive results may not be obtained for up to 6 months.²⁰⁵ Both FA and PCR assays are typically used by veterinary diagnostic laboratories to identify Leptospira species from urine samples. Neither of these tests will determine the infecting serovar. The sensitivity of detecting Leptospira shedding can be improved by performing two tests on a single sample.^205,²¹⁴ Evaluation of serovar-specific antibody titers from positive animals may aid in identification of the infecting serovar.

Second-voiding urine samples collected after the administration of IV furosemide are recommended for urine testing.^191,²¹⁵ Furosemide is administered at 0.5 to 1.0 mg/kg IV or IM, and the first-voided urine is discarded. A second urine sample is then collected after cleaning the vulva of gross debris. Approximately 10 mL of urine should be collected and stored on ice (not frozen) for transport to the diagnostic laboratory. Urine from 10 to 15 adult animals should be tested when evaluating a herd for endemic Leptospira serovar hardjo infection.

Biopsy or necropsy samples of renal tissue may be treated with Warthin-Starry or Levaditi silver stains for microscopic examination.¹⁹³ Immunoperoxidase staining was shown to be more sensitive for identifying Leptospira species in kidney and liver of naturally infected cattle than Levaditi silver stain.²¹⁶

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Treatment and Prognosis

Treatment of acute leptospirosis caused by non—host-adapted serovars should focus on the elimination of the bacteria, systemic support, and diuresis if renal involvement is observed. In vitro susceptibility has been demonstrated for several antibiotics that could be used in food-producing ruminants, including ampicillin, amoxicillin, penicillin G, erythromycin, tetracycline, tylosin, and tilmicosin.^203,²¹⁷^-²¹⁹ Oxytetracycline (10 to 15 mg/kg IM twice daily) and dihydrostreptomycin (12.5 mg/kg IM twice daily) have been recommended for treatment of acutely infected cattle.¹⁹¹ Nephrotoxicosis is a potential concern with this dosage of oxytetracycline in cattle with preexisting renal disease, and dihydrostreptomycin is not currently available for use in cattle in the United States. Penicillin (25,000 IU/kg IM twice daily) and sodium ampicillin (20 mg/kg IM twice daily) have been suggested for treatment, but the efficacy of these regimens in cattle remains unproved.¹⁹¹ In humans, doxycycline (100 mg every 12 hours for 7 days) has been shown to reduce the duration and severity of illness.¹⁸⁴

Intravenous or oral fluids and nonsteroidal antiinflammatory drugs (NSAIDs) may be indicated for systemic support. In animals with severe hemolysis, blood transfusion may be considered. Renal diuresis should be established in animals with hemoglobinuria or evidence of ARF from pigment nephrosis or interstitial nephritis. The prognosis for renal disease caused by leptospirosis is influenced by the virulence of the serovar involved, host immunity, and the extent of renal lesions. Cases with renal azotemia warrant a guarded prognosis because more than 75% of nephrons are affected in such cases, and chronic interstitial nephritis and fibrosis may occur after treatment of the acute disease.

Chronic renal infection with Leptospira serovar pomona in cattle can be eliminated with a single injection of dihydrostreptomycin (25 mg/kg IM), although spontaneous clearance of this serovar often occurs in cattle.^191,²⁰³ Conflicting data exist on the efficacy of this treatment in clearing renal infection with serovar hardjo.^220,²²¹ Long-acting oxytetracycline (20 mg/kg IM or SC, two doses 10 days apart) has been recommended to treat chronic leptospiral infections or reduce the risk of introduction of infected animals into a herd.¹⁸⁷ Oxytetracycline (20 mg/kg IM once), ceftiofur (2.2 mg/kg IM every 24 hours for five treatments), and tilmicosin (10 mg/kg SC once) have been shown effective in clearing renal shedding of L. borgpetersenii serovar hardjo from experimentally infected cattle.²²²

Prevention

Draining or fencing off standing water may reduce transmission. Maintaining a dry, clean environment may also help reduce exposure and infection. Limiting rodent and wildlife contact with cattle and their feed and water is often difficult to accomplish, but it reduces the potential for transmission of non—host-adapted leptospires.¹⁸⁹ For host-adapted Leptospira serovar hardjo, it is necessary to prevent or eliminate the renal carrier state in infected cattle in order to reduce transmission.

Vaccination is regarded as an effective means of preventing losses from leptospirosis. Conventional pentavalent (L. canicola, grippotyphosa, hardjo, icterohaemorrhagiae, and pomona), whole-cell, inactivated leptospiral vaccines are recommended in calves and adult cattle as an aid to prevent clinical disease caused by Leptospira species. However, these conventional pentavalent vaccines may not consistently prevent renal colonization and shedding after challenge with host-adapted L. borgpetersenii serovar hardjo (type hardjo-bovis).^223,²²⁴

A monovalent L. borgpetersenii serovar hardjo (type hardjo-bovis) vaccine (Spirovac, Pfizer Animal Health, New York) is licensed for the prevention of Leptospira serovar hardjo infection, including reproductive and renal tract colonization, and urinary shedding for up to 12 months. This vaccine stimulates an immune response characterized by IgG₁ and IgG₂ agglutinating antibodies, as well as antigen-specific T-cell production of interferon gamma (IFN-γ).^210,²²⁵^-²²⁷ The strong IFN-γ response is consistent with induction of a type 1 immune response and may be responsible for antibody class switching to IgG₂, which is a more potent opsonin than IgG₁.²²⁵ Combination pentavalent Leptospira vaccines have been developed that also promote high L. hardjo antibody titers, in addition to the other serovars contained in the vaccine (Vira Shield 6+L5^HB, Novartis Animal Health US, Greensboro, NC; Vista 5 L5 SQ, Intervet, Millsboro, Del). Because Leptospira species are largely extracellular pathogens, the relevant protective immune response appears to be antibody-mediated neutralization and opsonization during leptospiremia.^184,¹⁸⁵ There is no indication that cytotoxic immunity is a relevant immune response for protection or resolution of leptospirosis.

Although these vaccines help prevent colonization and shedding of leptospira serovar hardjo from the kidney, they are not effective in resolving current renal infection and elimination of the carrier state. Thus, vaccination at an early age followed by annual boosters is recommended to prevent initial renal colonization. Renal shedding in previously infected animals can be resolved by antibiotic treatment, and vaccination can be used to prevent future colonization.

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DR. CARL OSBORNE

UROLITHIASIS LABORATORY

DIETARY MANAGEMENT

Phosphatic Urolithiasis

Silica Urolithiasis

Calcium Carbonate Urolithiasis

WATER MANAGEMENT

URACHAL DISORDERS

Pathogenesis

Clinical Findings

Differential Diagnosis

Treatment

Prognosis

EVERSION OF THE BLADDER AND PROLAPSE OF THE BLADDER

Clinical Findings and Differential Diagnosis

EVERSION OF THE BLADDER

PROLAPSE OF THE BLADDER

Treatment and Prognosis

EVERSION OF THE BLADDER

PROLAPSE OF THE BLADDER

PELVIC ENTRAPMENT OF THE BLADDER

Clinical Findings

Differential Diagnoses

ENZOOTIC HEMATURIA

Clinical Findings

Clinical Pathology

Differential Diagnosis

Epidemiology

Pathophysiology

Necropsy Findings

Treatment and Prevention

URINARY TRACT INFECTION

Clinical Signs

Differential Diagnosis

Clinical Pathology

Pathophysiology

Epidemiology

Necropsy Findings

Treatment and Prognosis

Prevention and Control

AMYLOIDOSIS

Clinical Signs

Clinical Pathology

Differential Diagnosis

Pathophysiology

Necropsy Findings

Prognosis

GLOMERULONEPHRITIS

Clinical Signs

Differential Diagnosis

Clinical Pathology

Pathophysiology

Treatment and Prognosis

HEMOLYTIC UREMIC SYNDROME

Clinical Findings

Pathophysiology and Necropsy Findings

TUBULAR NECROSIS

METALS

ANTIMICROBIALS

ANALGESICS

PLANTS

ENDOGENOUS

MISCELLANEOUS

Clinical Signs

Differential Diagnosis

Clinical Pathology

Pathophysiology

ISCHEMIC AND HYPOXIC INJURY

TOXIC INJURY

Treatment and Prognosis

LEPTOSPIROSIS

Epidemiology

Clinical Findings

Pathophysiology

Diagnosis

Treatment and Prognosis

Prevention

CONGENITAL DEFECTS

Renal Defects

Ectopic Ureter