EQUINE RENAL SYSTEM

TOXIC NEPHROPATHIES

DIAGNOSIS

Acute renal failure should be suspected in patients showing more marked depression and anorexia than would be expected with the primary disease process and in patients that fail to produce urine within 6 to 12 hours of initiating fluid therapy. Rectal palpation in horses with ARF may reveal enlarged, painful kidneys in some cases. Enlargement can be confirmed by renal ultrasonography, which may also reveal perirenal edema, loss of detail of the corticomedullary junction, or dilation of renal pelves.^53-55

The diagnosis of ARF is confirmed on the basis of history, potential exposure to nephrotoxins, clinical signs, and laboratory findings. The increase in creatinine is often several-fold greater (e.g., up to 5 to 15 mg/dL) than for blood urea nitrogen concentration (BUN) (e.g., up to 50 to 100 mg/dL) resulting in a BUN/creatinine ratio that is often less than 10:1. Hyponatremia, hypochloremia, and hypocalcemia are usually present, and in more severe cases, hyperkalemia, hyperphosphatemia, and metabolic acidosis may also be detected.

In addition to assessment of the magnitude of azotemia and alterations in serum electrolyte concentrations and acid-base balance, urinalysis should be performed on all horses in which ARF is suspected. As mentioned previously, a low urine specific gravity (≤1.020) in the face of dehydration and gross or microscopic hematuria are common findings with ARF. In addition, evidence of more substantial proximal tubular damage, including increased urinary enzyme activity and glucosuria, may be detected in some horses, and significant proteinuria (urine protein/creatinine ratio >2:1; see Chronic Renal Failure) would support glomerular disease. Examination of urine sediment may reveal casts and increased numbers of erythrocytes and leukocytes, and the amount of urine crystals may be decreased. Increased fractional clearances of sodium and phosphorus are also common findings with ARF. It is important to remember that administration of IV fluids to healthy horses will also result in increased fractional clearances of sodium, chloride, and phosphorus.⁵⁶ Thus, electrolyte clearances are ideally determined using the initial urine sample voided after admission or a sample collected by catheterization (i.e., before urine substantially altered by fluid therapy).

The most accurate assessment of renal function involves measurement of glomerular filtration rate (GFR). GFR can be determined by performing timed urine collections (inulin and endogenous or exogenous creatinine clearances) or by assessing plasma disappearance of several compounds (sodium sulfanilate, phenolsulfonphthalein, or radiolabeled substances).⁵⁷ In a clinical setting, measurement of GFR in cases of ARF is rarely pursued because multiple measurements are required to assess changes in GFR, and prognosis for recovery is more likely related to the duration of decreased GFR rather than the magnitude of the decrease. Further, because of the inverse relationship between GFR and creatinine, changes in GFR can be more practically assessed by daily creatinine measurement.

Glomerular injury and tubular necrosis can be further confirmed by performing a renal biopsy. However, biopsy is rarely indicated in cases of ARF because the diagnosis is usually evident. Further, correlation between light microscopic findings and functional changes in animals with ARF has not been well established; thus, prognosis often depends more on response to treatment than results of renal biopsy. Immunofluorescent (IF) testing and electron microscopic (EM) examination are routinely performed on human renal biopsy samples to assess mechanisms of renal injury and extent of damage to glomerular and tubular basement membranes. If such detailed evaluation of renal biopsy tissue were also performed in horses with ARF, better information regarding etiopathogenesis and prognosis would likely be provided by the pathologist.

At present, renal biopsy is most often indicated in the evaluation of horses with ARF for which exposure to nephrotoxins or another underlying primary disease process is not apparent. However, renal biopsy should be approached cautiously because life-threatening hemorrhage is a potential complication. Biopsy of the right kidney with ultrasonographic guidance, usually through the seventeenth intercostal space, is the preferred procedure for renal biopsy.⁵⁸ Use of proper instrumentation (automatic or spring-loaded biopsy instruments) and adequate restraint (stocks and sedation) are important considerations. Renal tissue collected should be placed in formalin for histopathologic examination as well as frozen (or placed into additional media specified by the testing laboratory) for IF testing and EM examination. Although biopsy of the right kidney alone usually is adequate for assessment of the disease process affecting both kidneys, samples of the left kidney can also be collected by guiding the biopsy instrument through the spleen. Again, ultrasonographic guidance is important when collecting a biopsy from the left kidney or when biopsy of a specific area of either kidney is desired.

GENERAL PRINCIPLES OF TREATMENT

General principles of treatment of ARF in the horse are similar to those recommended for human patients.^59,60 Initial treatment should always focus on judicious fluid therapy to replace volume deficits and correct electrolyte and acid-base abnormalities. The magnitude of azotemia and serum concentrations of sodium, chloride, potassium, and bicarbonate should be monitored daily. Sodium and chloride replacement are often required in horses with polyuric ARF and can be accomplished by using 0.9% NaCl as the fluid administered or through electrolyte supplementation in grain feedings or as oral pastes. Serum potassium concentration in horses with nonoliguric ARF is often normal, and except for postrenal problems (e.g., obstruction or rupture), therapy intended to lower serum potassium is usually not necessary. Similarly, it is usually unnecessary to correct the mild hypocalcemia that can accompany ARF in horses.

After correction of volume deficits and electrolyte and acid-base abnormalities, an attempt should be made to determine if the animal is oliguric or nonoliguric (polyuric) because the prognosis for recovery appears to be more favorable with nonoliguric ARF. This often becomes apparent by simple observation: oliguric horses fail to produce expected amounts of urine in the initial 12 to 24 hours of IV fluid therapy, and the bedding remains dry, whereas nonoliguric horses repeatedly void moderate volumes of dilute urine during the initial 6 to 12 hours of treatment. Further, edema can develop rapidly in horses with oliguric ARF. In horses with prerenal azotemia rather than intrinsic ARF, creatinine should decrease by at least 30% to 50% within the initial 24 hours of fluid therapy. In contrast, creatinine remains unchanged, or may even increase, with ARF.

In severely ill patients, especially those with vasomotor nephropathy, systemic blood pressure (BP) can be monitored to confirm that fluid therapy has been adequate to restore BP. Some horses may remain hypotensive (systolic BP <80 mm Hg) despite administration of large volumes of IV fluids because fluid may be accumulating extravascularly as edema or a third space fluid. If systemic BP remains low, hypertonic saline, dobutamine, or other pressor agents may be needed to restore BP and glomerular filtration. Fluid and sodium replacement in horses with oliguric renal failure and normal systemic BP must be monitored closely because, as previously mentioned, overzealous fluid administration to horses with oliguric or anuric ARF will result in edema formation, which is often initially noticed in the conjunctiva (Fig. 34-1).

Fig. 34-1 Severe conjunctival edema from intravenous (IV) fluid therapy in a 3-year-old Arabian with oliguric acute renal failure (ARF). The ARF and a multifocal granulomatous pneumonia occurred after IV administration of an approved immunomodulator.

In addition to regular assessment of attitude, vital parameters, packed cell volume, and total plasma protein concentration, monitoring should also include measurement of body weight once or twice daily (patients should not gain weight after rehydration) and comparison of fluid input with fluid (urine) output. Although there is no convenient method of collecting all urine voided by ambulatory foals or mares, urine output can be rather easily quantified in male horses by placing a urine collection device around the abdomen.⁶¹ When desired, monitoring urine output in critically ill foals and mares can be accomplished by use of an indwelling Foley catheter and urine collection bag (closed system), but ascending infection is a risk. Finally, central venous pressure (CVP) can also be monitored as a more precise measure of fluid balance in critical patients. CVP is measured with a manometer, with the baseline at the level of the right atrium, attached to an IV catheter placed into the anterior vena cava via the jugular vein (normal CVP in horses, <8 cm H₂O).

In horses that remain oliguric after 12 to 24 hours of appropriate fluid and electrolyte replacement and restoration of systemic BP, furosemide at 1 mg/kg intravenously [IV] every 2 hours should be administered. Unfortunately, furosemide treatment is often ineffective in increasing renal blood flow, GFR, and tubular flow in horses with ARF.^60,62 Continuous infusion of furosemide at 0.12 mg/kg/hr, preceded by a loading dose of 0.12 mg/kg IV, was considered superior to intermittent use in one study.⁶³ If urine is not voided after the second dose, administration of mannitol (1 mg/kg as a 10% to 20% solution) and/or a dopamine infusion (3 to 7 μg/kg/min IV) can be instituted. Dopamine administration should only be performed in a hospital setting in which heart rate and BP can be monitored frequently to avoid development of tachycardia and hypertension. Use of dopamine for selective renal vasodilatory and natriuretic actions has recently been called into question because most studies in humans have not demonstrated prevention of ARF in high-risk patients or improved outcome in those with established ARF.⁶⁴ Further, the drug may precipitate serious cardiovascular and metabolic complications in critically ill patients. If these treatments are successful in converting oliguria to polyuria (may require 24 to 72 hours), they can be discontinued, but maintenance of urine production must be monitored closely over the next few days. Fortunately, the majority of horses with ARF resulting from ATN are nonoliguric rather than oliguric, and administration of furosemide, mannitol, or dopamine is not needed in most of cases of nonoliguric ARF.

When this treatment approach to oliguria remains unsuccessful for more than 72 hours, the prognosis becomes grave. One study of horses with colic or colitis found that horses with persistent azotemia after 72 hours of fluid therapy were three times as likely to die or be euthanized as the horses without persistent azotemia.⁶⁵ However, dialysis therapy may be a further treatment option in select patients. Hemodialysis has been successfully used to treat two adult horses with myoglobinuric ARF^66,67 and a neonatal foal with oxytetracycline-induced ARF.⁴¹ Peritoneal dialysis has been attempted in a few horses with nephrotoxic-induced ARF; however, omental plugging of the catheter has limited its success, and special dialysis catheters are needed for effective fluid exchange. Pleural dialysis is another option for which fluid exchange is less problematic. Hemodialysis or dialysis would likely be most effective in horses with nephrotoxic ARF, whereas vasomotor nephropathy is best treated by addressing the predisposing condition and instituting appropriate fluid therapy.

After volume deficits have been restored and polyuria has been achieved, patients usually require only continued fluid therapy (0.9% NaCl or another balanced electrolyte solution, 40 to 80 mL/kg/day) to promote a continued decrease in creatinine. Fluid therapy may need to be continued (20 to 40 mL/kg/day) for several days until creatinine returns to the normal range or a steady-state value and the horse is eating and drinking adequate amounts. Supplementation with oral electrolytes (1 to 2 oz NaCl twice daily) will also promote greater fluid intake and diuresis. Potassium supplementation (1 oz KCl twice daily) may also be required because the diuresis also results in kaliuresis. When horses remain anorectic during treatment, addition of 50 to 100 g dextrose/L fluids can provide needed calories, and if anorexia persists for several days, caloric intake may need to be provided by nasogastric tube feeding or total parenteral nutrition.

Within the week after fluid therapy is discontinued, creatinine should be measured again to ensure that it has not increased. Occasionally, creatinine may not decrease to below 2 to 3 mg/dL despite continued fluid therapy. As long as the horse is eating and drinking well, IV fluids can be discontinued. In some horses, further recovery will be manifested as a return of creatinine to the normal range within the next couple of months, whereas in other patients a persisting elevation in creatinine indicates a permanent loss of renal function.

CHRONIC RENAL FAILURE

THOMAS J. DIVERS

Chronic renal failure (CRF) in the horse may be divided by clinical and pathologic findings into two broad categories: primary glomerular disease and primary tubulointerstitial disease.^68,69 However, pathology in one portion of the nephron usually leads to altered function and eventual pathology in the entire nephron. Thus, CRF is an irreversible disease process characterized by a progressive decline in GFR. However, the rate of decline in GFR is variable between affected horses, making the short-term (e.g., months to 2 years) prognosis guarded to favorable while the long-term prognosis remains poor.

Primary glomerular diseases that can lead to CRF in horses include glomerulonephritis, nonspecific glomerulopathy, renal glomerular hypoplasia, and amyloidosis. Primary tubulointerstitial diseases causing CRF include incomplete recovery from acute tubular necrosis (ATN), pyelonephritis, nephrolithiasis, hydronephrosis, renal dysplasia, and rarely, papillary necrosis. Collectively, the latter disorders produce pathology categorized as chronic interstitial nephritis. Unfortunately, because renal disease is often advanced when horses are first presented for clinical evaluation, the inciting cause leading to CRF may be difficult to ascertain, and end-stage kidney disease (ESKD) may be the pathologic diagnosis. The inciting cause may more likely be discerned from the history (long term) rather than clinical findings at presentation, especially for primary tubulointerstitial diseases. Adjunctive diagnostic evaluation, including laboratory assessment, renal ultrasonography, and renal biopsy, may provide further evidence to document the inciting cause.

CAUSES

Proliferative Glomerulonephritis

Proliferative glomerulonephritis (GN), indicating increased cellularity of the glomerular tufts consequent to influx of inflammatory cells and proliferation of mesangium, is the most common glomerular disease causing CRF in horses. It is thought to result from deposition of circulating immune complexes along the glomerular capillaries or in situ formation along the glomerular basement membrane (GBM) (Fig. 34-2). Deposition of immune complexes causes activation of complement and vasculitis (type III hypersensitivity response). In one study, deposits of immunoglobulin G (IgG) and complement along the GBM were found through immunofluorescent (IF) staining in a large percentage (22 of 53) of horses at necropsy.⁷⁰ However, only 1 of these 53 horses developed CRF. Thus, although immune (antigen-antibody) complex deposition and subclinical GN may be common in horses, progression to CRF appears to be an infrequent occurrence. In this necropsy survey the predominant IF staining pattern was granular (patchy deposits of immune complexes and complement along GBM), but linear deposits were found in two horses. The latter finding was supportive of true autoimmune disease with more diffuse deposition of anti-GBM antibodies (type II hypersensitivity response) along the basement membrane antibody.

Fig. 34-2 Depiction of a subendothelial immunologic reaction suspected to occur in horses with streptococcal antigen-antibody—associated glomerulonephritis.

Streptococcal antigens have been suggested to be an important trigger for development of proliferative GN,⁷¹ and in one horse with CRF, streptococcal antigens were confirmed to be present in diseased glomeruli.⁷² Although equine infectious anemia virus is the only other antigen that has been detected in glomeruli of horses with proliferative GN,⁷³ subclinical GN likely accompanies other chronic infections in horses. It has also been suggested that equine GN may also be associated with either mixed or monoclonal cryoglobulins forming antibody-antibody glomerular depositis.⁷⁴ Fortunately, GN in most patients is rarely of clinical significance.

Chronic Interstitial Nephritis

Chronic interstitial nephritis (CIN) and fibrosis may be the most common cause of CRF in horses. Interstitial nephritis (tubulointerstitial disease) usually develops as a sequela to ATN consequent to exposure to nephrotoxins or vasomotor nephropathy. Other causes include drug-induced interstitial nephritis, urinary obstruction, pyelonephritis, renal hypoplasia/dysplasia, and papillary necrosis. Although the majority of horses that develop ARF attributable to these causes recover with apparently normal renal function (they remain nonazotemic), a few may survive with significant loss of renal functional mass and subsequently (often years later) develop signs of CRF attributable to CIN.⁷⁵ In horses less than 5 years of age that develop CRF that cannot be attributed to other causes, anomalies of development, including renal hypoplasia, dysplasia, and polycystic kidney disease, should be strongly suspected^69,76-78 (Fig. 34-3).

Fig. 34-3 Yearling thoroughbred with chronic renal failure caused by renal dysplasia. Failure to grow normally and lethargy were the primary complaints.

Clinical Signs and Laboratory Findings

The most common clinical sign observed in horses with CRF is weight loss.⁶⁹ A small plaque of ventral edema, usually between the forelimbs, is another frequent finding in horses with CRF.^69,87 Moderate polyuria and polydipsia (PU/PD) are usually present at some stage of the disease process, but PU/PD may not be noticed except by the astute owner or trainer.⁶⁹ Dysuria is generally not reported unless CRF is caused by pyelonephritis, which may be associated with bladder paralysis, lithiasis, and lower urinary tract infection (UTI). Normal equine urine is rich in crystals and mucus, making a prediction of urine abnormalities on gross observation difficult. However, hematuria or pyuria (gross or microscopic) may be reported in some, but not all, horses with pyelonephritis, urinary calculi, or neoplasia. Often, urine produced by horses with CRF is light yellow and transparent because it is relatively devoid of crystals and mucus. Accumulation of dental tartar, especially on the incisors and canine teeth (Fig. 34-4); melena; and oral ulcers are other findings that may be detected in horses with CRF. Growth in horses with renal hypoplasia, dysplasia, or polycystic kidney disease may be stunted. Although abdominal pain would be expected in horses with obstructive nephroliths or ureteroliths, colic signs are not often reported in horses with lithiasis producing obstruction of the upper urinary tract.^75,88

Fig. 34-4 Dental tartar caused by chronic azotemia in a 5-year-old standardbred with chronic renal failure.

Clinicopathologic findings in horses with CRF vary depending on appetite, diet, and the cause and severity of renal damage. Most horses with clinical signs of CRF have moderate to severe azotemia (creatinine usually ≥5 mg/dL). The BUN/creatinine ratio may vary, depending on protein intake, muscle mass, hydration, and degree of azotemia, but is usually 10:1 or greater. Mild hyperkalemia, hyponatremia, and hypochloremia are typically found in horses with CRF. Hypercalcemia, with serum concentrations sometimes exceeding 20 mg/dL, appears to be a laboratory finding with CRF that is unique to the equid. One early case series of CRF reported six of nine horses to be hypercalcemic⁸⁹; however, others have found a lower percentage to be hypercalcemic.⁹⁰ Hypercalcemia in horses with CRF is not a consequence of hyperparathyroidism,⁹¹ and its presence or absence appears to be more closely related to dietary intake than to the magnitude of azotemia. For example, four of four nephrectomized ponies fed alfalfa hay developed marked hypercalcemia,⁹² whereas serum calcium concentration remained within the normal range in four of four nephrectomized ponies fed grass hay (although filterable calcium did increase).⁶⁸ Similarly, hypercalcemia in horses with spontaneously occurring CRF can resolve within a few days of changing diet from alfalfa to grass hay.⁷⁸ Serum phosphorus concentration in horses with CRF is usually normal to decreased, and hypophosphatemia is more often detected with concurrent hypercalcemia. Hypermagnesemia may also be detected in some horses with CRF. Acid-base balance usually remains normal until CRF becomes advanced, but metabolic acidosis is a common finding in horses with end-stage disease.

Many horses with CRF are moderately anemic (packed cell volume, 20% to 30%) as a consequence of decreased erythropoietin production by the diseased kidneys. Those with CRF resulting from GN frequently have hypoalbuminemia and hypoproteinemia, and horses with advanced CRF of any cause may also have mild hypoproteinemia associated with intestinal ulceration. Hyperglobulinemia may be detected in horses with immune-mediated diseases or chronic pyelonephritis. Horses with CRF can also develop hypercholesterolemia and hypertriglyceridemia (hyperlipidemia), and a horse with advanced CRF occasionally may have grossly lipemic plasma.⁹³

Urinalysis findings may also vary depending on the cause of CRF. As mentioned, urine collected from horses with CRF is relatively devoid of normal mucus and crystals, making samples transparent. Further, urine specific gravity is typically in the isosthenuric range (1.008 to 1.014), although heavy proteinuria in an occasional horse with GN may produce values up to 1.020. Quantification of urine protein concentration (as for cerebrospinal fluid) is required to assess proteinuria accurately. Urine protein concentration in normal horses is usually less than 100 mg/dL, and the urine protein/creatinine ratio should be less than 1:1.^94,95 With significant proteinuria, urine protein/creatinine ratio is usually greater than 2:1.⁷² In the earlier stages of GN, excessive urine protein is primarily albumin, but with progression of glomerular pathology, an increasing amount of globulin is also lost in the urine. Horses with CIN usually do not have significant proteinuria. Hematuria (gross or microscopic) may be present with pyelonephritis, urinary calculi, or neoplasia and can produce trace proteinuria, but urine protein/creatinine ratio usually remains less than 2:1. Although horses with septic pyelonephritis would be expected to have pyuria (>5 leukocytes/high-power field) and significant bacteriuria on sediment examination, these findings are not consistently detected, and a urine sample should be submitted for quantitative bacterial culture in all horses with CRF. Usually, more than 10,000 colony-forming units per milliliter of urine are found with infection, although lower numbers do not always rule out septic pyelonephritis.

Diagnosis

A diagnosis of CRF is most often made in horses with azotemia and isosthenuria that present with a complaint of weight loss or decreased performance. As discussed earlier, determining the inciting cause of CRF can be difficult because the disease has often advanced to ESKD when horses are initially presented for evaluation. Urinalysis does not often reveal the cause of CRF, except in some horses with pyelonephritis. In theory, assessment of urine protein concentration and urine protein/creatinine ratio should be helpful in separating glomerular disease from tubulointerstitial disease, but in practice, these laboratory measures have not consistently been elevated in horses with histopathologic evidence of glomerulonephritis. However, detection of moderate to heavy proteinuria (urine protein/creatinine ratio >2:1) without hematuria provides support for glomerular disease.

Rectal examination may be helpful in determining the cause of CRF. Horses with pyelonephritis, as well as those with ureteral calculi, often have enlarged ureters that can be palpated dorsolaterally as they course through the retroperitoneal space. Although kidneys of horses with CRF are often small with an irregular surface, these changes are not always apparent on palpation of the caudal pole of the left kidney. The right kidney cannot usually be palpated in the horse unless it is greatly enlarged or displaced caudally by the liver or a mass. Ultrasonographic imaging is useful for evaluating kidney size and echogenicity and may reveal fluid distention (hydronephrosis, pyelonephritis, polycystic disease) or presence of nephroliths.^96-98 Horses with significant renal parenchymal damage and fibrosis often have loss of detail of the corticomedullary junction, and echogenicity of renal tissue may be similar or even greater than that of the spleen. In contrast, intravenous pyelography (IVP) provides little information in adult horses and its use is generally limited to foals less than 50 kg. When hematuria or dysuria accompanies CRF, cystoscopic examination can be helpful in determining the side (right vs. left) from which renal hematuria is originating and further allows assessment of the ureteral orifices and urine flow from each kidney.

As described under Acute Renal Failure, measurement of GFR provides the most accurate assessment of renal function, and repeated measurements at monthly or longer intervals can be useful to monitor rate of progression of CRF. It is also a useful measure to document a reduction in renal function in horses that are thought to have early CRF, before significant azotemia has developed. GFR can be measured by several methods, including urinary clearance of endogenous or exogenous creatinine, inulin, or technetium-99m diethylenetriamine pentaacetic acid (^99mTc-DTPA) (all require timed urine collections) or plasma disappearance of sodium sulfanilate, phenolsulfonphthalein, or radiolabeled compounds (e.g., ^99mTc-DTPA).^78,99-102 Assessment of renal function by nuclear scintigraphic imaging of the kidneys has also been described, but in horses this technique appears to be better for documenting decreased individual kidney function (i.e., with unilateral or asymmetric disease) than for quantitative assessment of GFR.^103,104 In most clinical settings, performing a 24-hour endogenous creatinine clearance is the most practical and economical method for measuring GFR. The major challenge is application of a urine collection device for collection of all urine produced. Once urine has been collected, a well-mixed sample is submitted to the laboratory, along with a sample of serum obtained during the collection period, and GFR is estimated by the following standard clearance formula:

where UF is urine flow (mL • min⁻¹) and bwt is body weight in kilograms.¹⁰⁰ GFR in horses with normal renal function ranges from 1.5 to 3.0 mL • kg⁻¹ • min⁻¹, and values less than 1.0 mL • kg⁻¹ • min⁻¹ are indicative of a decrease in GFR. Although repeated measurement of endogenous creatinine clearance provides useful information about the rate of decline in GFR in horses with CRF, simply measuring creatinine and assessing body condition at monthly or longer intervals are the most common methods used to evaluate the progression of CRF in affected horses.

The inciting cause of CRF can be confirmed in some horses by renal biopsy. As discussed under Acute Renal Failure, renal biopsy should be approached cautiously and pursued only if findings are likely to change treatment or prognosis. Treatment for CRF consists of supportive care, and the long-term prognosis is poor; therefore, renal biopsy is rarely indicated in horses with CRF. Further, most horses have rather advanced CRF at the time the disease is initially detected, and biopsy results in these patients may not provide useful information regarding the inciting cause.

Treatment

Treatment of horses with CRF is most likely to produce improved renal function if there is an acute, reversible component exacerbating CRF (i.e., acute on chronic syndrome). Similar to ARF, sudden exacerbation can be caused by exposure to nephrotoxins or vasomotor nephropathy secondary to diseases producing hypovolemia (e.g., diarrhea or sepsis causing volume depletion). Ascending urinary tract infection or obstruction can also exacerbate CRF. If an acute component is detected, it should be corrected rapidly (as described for ARF) with the goal of minimizing further loss of functional nephrons. In addition, surgical removal or fragmentation of stones may be indicated in horses with calculi thought to be disrupting urine flow.

In horses with relatively stable CRF, management changes should be kept to a minimum and, when necessary, made gradually. Treatment of horses with stable CRF consists of supportive care: providing sufficient fluids, electrolytes, and nutritional support.¹⁰⁵ Water should be available at all times, and salt can be provided freely as long as edema or hypertension is absent. If edema develops, salt should be restricted, even in the face of hyponatremia. In addition to creatinine, serum electrolyte concentrations and acid-base balance should be measured regularly (e.g., monthly or longer intervals). If serum sodium and chloride concentrations are decreased, 60 to 120 g (∼2 to 4 oz) of salt may be added to the feed, provided edema is not present. If metabolic acidosis is detected (e.g., blood pH <7.35 or serum bicarbonate concentration <20 mEq/L) and the patient is not edematous, sodium bicarbonate (NaHCO₃) powder (100 to 200 g/day) or a mix of NaHCO₃ and salt should be added to the diet. The goal of supplementation with salt and NaHCO₃ is to maintain serum electrolyte concentrations and acid-base balance within reference ranges. However, the effect of electrolyte supplementation on progression of CRF is unclear because high-salt diets may actually hasten the decline in GFR and exacerbate proteinuria in human patients with CRF.¹⁰⁶

Although no adverse effects of hypercalcemia in horses with CRF have been documented, decreasing calcium intake (e.g., replacing alfalfa or other legume hays with grass hay) may result in a return of serum calcium concentration to the normal range. The hypophosphatemia that usually accompanies hypercalcemia in horses with CRF may prevent mineralization of soft tissues. There appears to be no need for vitamin D supplementation in horses with CRF but regular administration of vitamin B complex, and anabolic steroids may be helpful to stimulate appetite. If appetite remains good, anabolic steroids may further limit muscle wasting and may increase packed cell volume (PCV). Attenuation of anemia in human and canine patients with CRF by administration of recombinant erythropoietin has been one of the most significant advances in management of CRF because it has eliminated the need for blood transfusions, improved exercise capacity, and decreased morbidity associated with the uremic syndrome.¹⁰⁷ In an occasional horse with advanced CRF, marked hyperlipemia may develop, and administration of heparin (40 to 100 IU/kg subcutaneously [SC] twice daily) may stimulate lipoprotein lipase and decrease plasma triglyceride concentration.¹⁰⁸ However, this treatment is not without risk because it may cause a further decline in PCV and potentiate bleeding tendencies in a uremic patient. NSAIDs and corticosteroids are best avoided in horses with CRF attributable to primary tubulointerstitial disease. If these drugs are essential for treatment of a complicating problem, they should be used judiciously.

Treatment of CRF consequent to GN appears to be even less rewarding than treatment of CRF caused by tubulointerstitial disease (CIN). Immunosuppressive therapy has been of limited benefit in slowing the progression of the disease and may even hasten weight loss. For patients with significant edema, treatment with diuretics may result in transient improvement, and plasma transfusions may be of temporary benefit to horses with edema and hypoalbuminemia.

As CRF progresses, partial anorexia and lethargy lead to more rapid loss of body condition. Thus, nutritional management aimed at maintaining body condition is probably the most important aspect of supportive care of horses with CRF. Increasing carbohydrate (grain) intake and adding fat to the diet are recommendations to increase caloric intake. Fat can be added by feeding corn oil (up to 16 oz/day) or a commercial fat supplement. Increased intake of omega-3-fatty acids (e.g., available in linseed oil or flaxseed oil) has been demonstrated to slow the progression of renal failure in experimental models, but potential benefits in spontaneously occurring CRF are less clear.^109,110 Over the past two decades, restricting dietary protein intake by human and veterinary patients with CRF was thought to have beneficial effects¹¹¹; however, the current recommendation is to provide adequate amounts of dietary protein and energy to meet or slightly exceed predicted requirements while maintaining a neutral nitrogen balance.¹¹² In horses with CRF, adequacy of dietary protein intake can be assessed by the BUN/creatinine ratio; values greater than 15:1 suggest excessive protein intake, and values less than 10:1 may indicate protein-calorie malnutrition. Finally, an important but often overlooked aspect of nutritional management of horses with CRF is provision of a highly palatable diet. Feeding smaller meals more frequently and varying the diet (e.g., offering various types of concentrate feeds as appetite may vary from day to day) are helpful methods to increase food intake.

Additional treatments for CRF in human patients include antihypertensive agents including diuretics, β-adrenergic blockers, and angiotensin-converting enzyme (ACE) inhibitors.¹¹³ Use of ACE inhibitors may have an additional benefit of limiting proteinuria.¹¹⁴ Currently, little is known about the roles of systemic or intrarenal hypertension in progression of renal disease in horses, and there are no reports of potential benefits of use of antihypertensive medications in horses with CRF. Finally, efforts are under way to examine the roles of mediators of inflammation in development of renal fibrosis, with the hope that future specific interventions may be developed to limit the progressive interstitial fibrosis that occurs in all patients with CRF.¹¹⁵

Horses with end-stage CRF often develop oliguria and uncontrollable metabolic acidosis. At this stage, CRF can only be managed by hemodialysis or peritoneal/pleural dialysis. However, pursuit of either hemodialysis or peritoneal dialysis in horses with CRF is impractical because, even when successful, dialysis prolongs the life of the patient for only a short time.

Prognosis

The progressive loss of nephron function that is characteristic of CRF precludes successful long-term treatment in horses. However, many horses with early CRF may be able to continue in performance or live as a pet for months to a few years. In general, as long as creatinine remains less than 5.0 mg/dL and the BUN/creatinine ratio is less than 15:1, affected horses seem to maintain a reasonably good attitude, appetite, and body condition. However, once creatinine exceeds 5.0 mg/dL, the rate of progression of CRF appears to accelerate, and signs of uremia (e.g., anorexia, poor hair coat, loss of body condition) become more apparent over a few weeks to months. Although this threshold value for creatinine is a useful figure for offering an initial prognosis for most horses with CRF, it is important to remember that progression of CRF is highly variable between affected animals. Thus, each case must be handled on an individual basis, with the emphasis on maintenance of body condition until humane euthanasia may become necessary.

URINARY TRACT INFECTIONS

THOMAS J. DIVERS

Urinary tract infections (UTIs) can be anatomically divided into two categories: (1) those affecting the upper urinary tract (kidneys and ureters) and (2) those involving the lower urinary tract (bladder and urethra). Lower UTI in horses usually results from anatomic or functional causes of abnormal urine flow, especially bladder paralysis (see Urinary Incontinence). Although recognized less frequently, upper UTI is often a more serious, potentially life-threatening problem. In horses, UTI is also frequently accompanied by urolithiasis and partial obstruction. With the exception of single, large cystoliths (that predispose affected horses to lower UTI), it is often difficult to determine whether development of nephroliths, ureteroliths, multiple small cystoliths, and urethroliths was a predisposing cause or a consequence of UTI. The pathophysiology, diagnosis, and management of equine UTI has recently been extensively reviewed.¹¹⁶

RISK FACTORS AND CAUSES

The most common risk factors for development of UTI in horses are bladder paralysis, concurrent urolithiasis, and urethral damage (e.g., foaling trauma in mares, neoplasia or habronemiasis in stallions and geldings). The shorter urethra and its location near the anus also increase the risk of lower UTI in healthy females. For example, silent lower UTIs and pyelonephritis, resulting from infection with bacteria shed from the GI tract, can develop in prepubertal girls and during pregnancy or after menopause in adult women.¹¹⁷ This increased risk at certain times in women has been further attributed to a lack of estrogen, a hormone that appears to be important for production of glycosaminoglycans that cover uroepithelial surfaces and inhibit attachment of bacteria.¹¹⁸ Whether fillies or pregnant mares are at increased risk for UTI has not been studied. However, horses with bladder paralysis (detrusor dysfunction) or decreased urethral sphincter tone (from trauma or neurologic disease) are clearly at greater risk of UTI than horses with normal detrusor and urethral sphincter function. Finally, because bladder catheterization cannot be performed in a sterile manner because of normal bacterial flora in the vestibule and distal urethra, contamination of the lower urinary tract is an accepted risk of this procedure. Nevertheless, development of lower UTI is an unlikely complication of bladder catheterization in otherwise healthy animals because host defense mechanisms, including urine flow, are highly effective in eliminating contaminating bacteria. However, when urethral or bladder mucosa has been damaged or when urine stasis (bladder paralysis) is present, bladder catheterization has a greater risk of producing UTI.

In a group of horses with neurologic bladder dysfunction complicated by UTI, Escherichia coli, Staphylococcus species, Corynebacterium species, and Pseudomonas aeruginosa were the microbes isolated most frequently.¹¹⁹ In my experience, E. coli, Proteus mirabilis, Klebsiella species, and Enterobacter species are the most common pathogens isolated from individual horses with UTI. P. aeruginosa can cause lower UTI in some horses, but it can also be isolated from the urethra of many clinically normal horses. Gram-positive organisms are less frequent causes of UTI in horses, although Staphylococcus and Corynebacterium species are occasionally identified pathogens.¹²⁰ In horses with abnormal urine flow (e.g., with uroliths) or instrumentation of the urinary tract (e.g., indwelling bladder catheters, ureteral stents), UTI with Enterococcus species (formerly Streptococcus faecalis) may also develop. Similarly, lower UTI with Candida species develop commonly in recumbent neonatal foals receiving broad-spectrum antibacterial therapy.

Treatment

Treatment of UTI consists of proper antimicrobial therapy and correction, if possible, of predisposing anatomic or functional causes. Selection of the appropriate antimicrobial agent is best determined by prior knowledge of the following:

Susceptibility patterns of the causative agent(s)

Concentration of the antibiotic in renal tissue and urine

Activity of the antibiotic at different pH values

Ease of administration

Toxicity

Expense

Compatibility with other antimicrobial drugs

Recommended antimicrobial agents for treatment of UTI in horses are discussed next. It should be emphasized that in vitro resistance to a particular antibiotic may not preclude successful treatment with the drug, as long as high concentrations are achieved in urine. Similarly, in vitro susceptibility does not always guarantee a successful response to treatment. For example, Enterococcus species are routinely found to be susceptible to trimethoprim-sulfa combinations; however, this pathogen is inherently resistant to these combinations in vivo.¹³⁰

ECTOPIC URETER

THOMAS J. DIVERS

Although rare, ectopic ureter is the most frequently reported developmental anomaly of the equine urinary tract. Of the cases reported, almost 90% have been fillies, and the primary complaint is urinary incontinence and perineal dermatitis (urine scalding).^154-157 However, this gender distribution may reflect easier recognition of urinary incontinence in females rather than a true gender predilection. In the male, intermittent urine dripping from the end of the penis is less easily recognized; further, urine entering the pelvic urethra may pass retrograde into the bladder.

Diagnosis

Ectopic ureter should be suspected in young horses with incontinence observed shortly after birth. Renal function is usually normal, but the affected ureter may be extremely dilated. In young foals (e.g., <50 to 75 kg) an excretory urogram (after IV administration of contrast agent) or pyelography (after percutaneous injection of contrast agent into renal pelvis via ultrasonographic guidance) may aid in diagnosis of ectopic ureter.^157,158 Unfortunately, most patients are not presented until they are too large for this procedure to be performed (Fig. 34-5). Ultrasonographic examination may reveal mild dilation of the renal pelvis on the affected side. Vaginoscopic and cystoscopic examinations should also be pursued in older foals to determine whether the problem is unilateral or bilateral, and when unilateral, to determine which ureter is ectopic. In the latter case, cystoscopic examination should reveal urine entering the bladder from only one normal ureteral opening, located at either 2 or 10 o’clock in the bladder neck. Urine can be seen squirting from normal ureteral openings every 20 to 30 seconds. Observation of normal bouts of voiding, in addition to incontinence, further supports a unilateral problem. To determine the location of the opening of the ectopic ureter, visual examination of the vestibule and vagina (using a blade speculum) should be performed initially to look for intermittent urine flow from the area of the urethral papilla. Ectopic ureteral openings are usually not apparent unless urine flow is seen. Intravenous administration of dyes including sodium fluorescein (10 mg/kg IV; yellow-green color), indigotindisulfonate (indigo carmine, 0.25 mg/kg IV; blue-purple color), azosulfamide (2.0 mg/kg IV; red color), or phenolsulfonphthalein (1.0 mg/kg IV; red color) to discolor the urine may aid in location of ectopic ureteral openings.^154,155

Fig. 34-5 Urine scalding in an 8-month-old thoroughbred filly with a left ectopic ureter. The filly recovered after a nephrectomy.

Treatment

If the ectopic ureter is unilateral, creatinine is normal, and ultrasonographic examination of the opposite kidney appears normal, the preferred treatment may be surgical removal of the kidney on the affected side and ligation of the ureter. Nephrectomy may produce an increase in creatinine (0.5 to 1 mg/dL) for a few days, but creatinine returns to the prenephrectomy value within a week. If both ureters are ectopic, which is not unusual, implantation of the distal ureters into the bladder neck should be attempted. Several surgical techniques have been described, but complications can include ascending infection, resulting from dilated ureters, and development of adhesions.^154-157

NEOPLASIA

THOMAS J. DIVERS

Neoplasia of the urinary tract is rare in horses. Primary kidney neoplasms include renal cell carcinoma and nephroblastoma, with the former being the most common tumor of the kidney.¹⁵⁹ Renal cell carcinoma (or adenocarcinoma) occurs more frequently in older horses, but nephroblastomas may be detected in young horses. Squamous cell carcinoma is the most common bladder tumor, but horses may also develop transitional cell carcinoma.^160,161 Fibromatous polyps may also occur in younger horses, but bladder tumors usually develop in middle-age to older horses. Adenoma, lymphosarcoma, hemangiosarcoma, and melanoma may also involve the kidneys and, on rare occasions, the bladder.^162,163

Clinical Signs and Diagnosis

Clinical signs in horses with renal neoplasia include hematuria, weight loss, and recurrent colic. Sudden death may occur if the neoplasm hemorrhages into the abdomen or thorax. Renal tumors may result in marked enlargement of the kidneys such that both left and right kidneys may be found on rectal palpation. In other cases, tumors may be small, circumscribed lesions within a kidney (Fig. 34-6) that cannot be felt during rectal palpation. Small tumors may also be difficult to visualize on ultrasonographic examination. The diagnosis is based on history, clinical signs, and ultrasonographic findings (Fig. 34-7). Affected horses usually are not azotemic, but mild anemia may be detected when gross hematuria is observed. Although neoplastic cells are unlikely to be found in urine, cytologic examination of urine sediment is warranted. Nephroblastoma usually remains limited to the kidney, but renal cell carcinomas typically metastasize to the liver and lungs. Thoracic radiographs are helpful in detecting pulmonary metastases. With ultrasonographic guidance, the tumor can usually be biopsied and a definitive diagnosis established.

Fig. 34-6 Cut section of the left kidney from a 25-year-old horse with chronic weight loss, hematuria, and severe anemia. The kidney appeared normal, except for a small, 4 × 5—cm carcinoma with surrounding hemorrhage.

Fig. 34-7 Sonogram of the left kidney area of a 19-year-old horse with chronic hematuria. A 26 × 20 × 19—cm echocavitated mass (renal carcinoma) originates from the left kidney.

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In addition to hematuria and weight loss, horses with bladder tumors may also present with pollakiuria and stranguria. With bladder tumors, a mass can usually be palpated on rectal examination, but it should not be confused with a cystolith or accumulation of sabulous concretions in the ventral aspect of the bladder. Horses with gross hematuria may be mildly anemic but usually are not azotemic. Other than hematuria and associated proteinuria, urinalysis results are often unremarkable; however, with bladder tumors, cytologic examination of urine sediment is more likely to reveal neoplastic cells than with renal tumors.^160,164 A diagnosis of bladder neoplasia may be confirmed by cystoscopic examination and biopsy (Fig. 34-8).

Fig. 34-8 Cystoscopic image of a squamous cell carcinoma of the bladder causing intermittent hematuria in a 14-year-old warmblood mare. The endoscope has been passed beyond the tumor and retroflexed to provide a view directed caudally; a pool of urine is in the foreground, and the tumor can be seen in the ventral aspect of the bladder neck.

In addition, tumors may metastasize, and the initial signs may be as varied as a lameness¹⁶⁵ or an ulcerated mass on the premaxilla.¹⁶⁶ Tumors can also metastasize to the lung.¹⁶⁷

Multiple myeloma involving the kidney resulted in hypercalcemia and a high serum parathyroid hormone—related protein concentration.¹⁶⁸ Hypoglycemia was the chief clinical sign in a 6-year-old horse with renal cell carcinoma, which was producing insulin-like growth factors.¹⁶⁹

Treatment

The treatment of choice for unilateral renal neoplasia is nephrectomy. Unfortunately, most cases of renal cell carcinoma have metastasized by the time the diagnosis is made, and surgical intervention is of little benefit to horses with disseminated disease. Thus, careful evaluation for metastatic disease should be pursued before contemplating a nephrectomy. Treatment of bladder tumors includes surgical excision and/or topical chemotherapy using either 5-fluorouracil or triethylenethiophosphoramide.¹⁶⁰

RENAL AND URETERAL CALCULI

Renal and ureteral calculi can produce partial or complete obstruction of one or both sides of the upper urinary tract. Nephroliths usually develop within or adjacent to the renal pelvis, and obstruction can lead to hydronephrosis. Most ureteroliths likely originate as nephroliths that pass into the ureter, where they become lodged and enlarge over time. Ureteral stones have a propensity to lodge in the distal ureter and can sometimes be palpated rectally dorsal and lateral to the bladder neck. Occasionally, small nephroliths may pass all the way down the ureter into the bladder; unlike their human counterparts, affected equine patients are rarely recognized to manifest renal colic.^170,171 Renal and ureteral calculi are most often composed of calcium carbonate crystals; calcium phosphate stones may occasionally develop. Although usually not recognized clinically, a nidus of damaged tissue (e.g., interstitial inflammation, infection, or fibrosis; area of medullary crest necrosis adjacent to renal pelvis) is likely necessary for initiation of stone formation. Anomalies of development (e.g., renal hypoplasia, dysplasia, polycystic disease) or prior exposure to nephrotoxins could also provide a nidus for stone formation.

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Bilateral nephrolithiasis and ureterolithiasis has been best described in a series of young adult racehorses, and development of subclinical medullary crest necrosis as a result of NSAID use was a suggested risk factor¹⁷²; this was also seen in a 2-year-old gelding.¹⁷³ When both sides of the upper tract are affected, the condition typically progresses to CRF before horses are presented for evaluation (Fig. 34-9). As described for CRF, the most common presenting complaint is weight loss, but polyuria and poor performance may be earlier complaints in competitive horses. Establishing a diagnosis of urolithiasis causing unilateral upper tract obstruction is more challenging because clinical signs are mild (recurrent colic) or nonexistent and azotemia is usually absent. In fact, unilateral upper tract stones may be detected as incidental necropsy findings in horses of all ages. In horses with clinical signs, careful rectal palpation may reveal a turgid ureter and presence of a ureterolith. When passed from the upper tract into the bladder, small uroliths may be voided without problem or may cause urethral obstruction in males. Horses with repeated bouts of urethral obstruction should be thoroughly evaluated for presence of upper tract disease.

Fig. 34-9 Urinary tract removed from a 5-year-old standardbred with chronic renal failure caused by intermittent or persistent obstruction by renal and ureteral stones. Note the location of the ureteral obstruction near the bladder. This is the most common site for the obstruction to occur.

In horses with bilateral disease leading to CRF, azotemia and isosthenuria are present. As already mentioned, azotemia is usually absent with unilateral obstruction. With either scenario, gross hematuria is uncommon unless stones have been passed into the bladder or urethra, but urinalysis usually reveals pigmenturia, and microscopic hematuria is confirmed by examination of urine sediment. Although UTI usually is not present with upper tract obstruction consequent to lithiasis at the initial evaluation, it may develop with catheterization or other instrumentation used for relief of the obstruction. Thus a quantitative urine culture should be considered part of the minimum database, especially if pyuria or bacteriuria is detected on sediment examination. Transabdominal ultrasonography is a valuable tool for detection of nephroliths, dilation of the renal pelvis (or complete hydronephrosis), and fibrosis (increased echogenicity) within the kidney.^174-176 However, small nephroliths (<1 cm in diameter) occasionally can be missed despite a complete ultrasonographic examination. Transrectal ultrasonography is also useful for detection of ureteral dilation and lithiasis.

If upper urinary tract obstruction is diagnosed before development of more severe azotemia (creatinine >5.0 mg/dL), surgical removal is recommended. A nephrotomy and/or ureterotomy may be required.^170,172 When equipment is available, electrohydraulic lithotripsy is the preferred technique for removal of ureteral stones.¹⁷⁷ This procedure involves passing an endoscope into the ureter until the stone can be seen, then advancing a lithotriptor through the biopsy channel of the endoscope until the end touches the ureterolith (Fig. 34-10, A). An irrigating solution is pumped through the endoscope to distend the distal ureter, and an electrical impulse delivered by the lithotriptor causes a shock wave at the surface of the stone. Because the majority of calcium carbonate stones are inherently fragile,¹⁷⁸ fragmentation by lithotripsy is usually rapid (Fig. 34-10, B), and remaining fragments are flushed distally by further infusion of irrigating solution (Fig. 34-10, C). Before surgical intervention is pursued, both kidneys should be thoroughly evaluated for evidence of other stones because upper tract lithiasis is often bilateral.

Fig. 34-10 Endoscopic images of a ureterolith completely obstructing the left ureter. A, Immediately before electrohydraulic lithotripsy. B, After partial fragmentation. C, After complete removal. White instrument is a ureteral stent placed to facilitate passage of the ureteroscope, and gray instrument (in A and B) is the lithotriptor touching the surface of the ureterolith.

In addition to intermittent signs of mild colic, unilateral nephroliths may occasionally cause intermittent or persistent gross hematuria. In the absence of azotemia and evidence of disease of the contralateral kidney, unilateral nephrectomy is the treatment of choice for obstructing nephroliths and remains a reasonable alternative to lithotripsy for treatment of unilateral ureteroliths¹⁷⁹ (Figs. 34-11 and 34-12).

Fig. 34-11 Left kidney of a 12-year-old thoroughbred that presented with a complaint of intermittent hematuria. Right kidney appeared normal on ultrasound examination, and renal function was normal.

Fig. 34-12 Left kidney shown in Fig. 34-11 was removed with the horse anesthetized but strapped to the surgery table in an upright position. This is the preferred surgical position for nephrectomy or nephrotomy in adult horses.

CYSTIC CALCULI

Although occurrence is rare compared with other species, cystolithiasis is the most common form of urolithiasis in horses, and intact males appear to be at greater risk.^171,180 Calculi that develop in the bladder are usually single, large spiculated stones composed of calcium carbonate crystals.^178,180,181 Less often, stones are a mix of calcium carbonate and calcium phosphate crystals; these stones often have a smooth surface and are more resistant to fragmentation.¹⁸² Risk factors for development of bladder stones in horses are not well understood, but anatomic defects (e.g., diverticuli) or suture material persisting from prior bladder surgery may predispose horses to cystic calculi. Although bacteria can often be detected by culture of the center of equine calculi, their role in stone formation is unclear.¹⁷¹ Considering that normal equine urine is rich in calcium carbonate crystals, it is surprising that cystoliths are not more common in horses than in ruminants or small animals. Their low occurrence can likely be attributed to the large amount of mucus that is also present in horse urine. Mucus, produced by glands in the renal pelvis and proximal ureter, appears to act as a lubricant to prevent adherence of crystals to uroepithelium.

The most common clinical sign exhibited by horses with cystic calculi is hematuria after exercise. Pollakiuria, stranguria, or incontinence may also be observed. Less frequently, dysuria may be caused by accumulation of urine sediment in the ventral aspect of the bladder. This condition, sabulous urolithiasis, usually develops as a result of bladder paralysis.¹⁸³ Urinary incontinence is usually present in horses with sabulous urolithiasis, and prognosis is guarded to poor because of underlying detrusor dysfunction.

Presence of a cystolith can be confirmed by rectal examination. It is important to remember that most bladder stones can be palpated with only the hand and wrist in the rectum. As a result of frequent urination, the bladder is usually small, and cystic calculi can be missed if the examiner passes quickly beyond the calculus during the rectal examination. Careful palpation may also allow discrimination between soft-tissue masses of the bladder (neoplasia) and sabulous urolithiasis. With the latter, firm sediment is usually palpated well over the pelvic brim in the ventral aspect of a distended bladder. Manipulation of the bladder is accompanied by incontinence, and sabulous uroliths may be indentable when palpated after the bladder has been emptied via catheterization. Although rarely needed to confirm the diagnosis, ultrasonographic examination of the entire urinary tract should be considered because calculi may be present in multiple locations. Because UTI can sometimes accompany cystolithiasis, urinalysis and a quantitative urine culture are warranted during the initial evaluation of all horses with bladder stones.

Treatment of cystic calculi usually consists of surgical removal accompanied by a 7- to 10-day course of postoperative antibiotic treatment. Cystotomy can be performed via celiotomy or a pararectal approach (Gäkel’s operation) or the stone can be removed after fragmentation with a lithotriptor passed via a perineal urethrotomy.^182,184,185 In mares, urethral sphincterotomy after epidural anesthesia with xylazine has been advocated as a practical method for stone removal. However, with sedation and epidural anesthesia, manual distention of the urethra often allows several fingers or a small hand to be passed into a mare’s bladder, and depending on size, the stone can be retrieved intact or after fragmentation. Placing the cystolith into a sterile rectal sleeve or surrounding it with a similar smooth plastic material allows easier removal of spiculated stones and fragments. If available, electrohydraulic or pulsed-dye-laser lithotripsy may be the least traumatic method of fragmentation and removal of bladder stones in both genders; however, success may be limited by the ability to lavage all stone fragments from the bladder.^186-190

Historically, risk of recurrence after surgery has been considered low; however, in a series of 68 cases of urolithiasis (at all levels of urinary tract), 12/29 horses (41%) with follow-up had recurrence 1 to 32 months after surgery. Recurrence was more common with perineal urethrotomy than cystotomy and was attributed to the former’s inability to remove all fragments completely by lavage.¹⁷¹ This relatively high recurrence rate indicates that postoperative management changes are warranted to decrease risk of future stone formation. Changing from a legume to a grass hay is the most practical recommendation to decrease urinary calcium excretion. Urinary acidification with ammonium chloride (50 to 200 mg/kg/day PO) or ammonium sulfate (200 to 300 mg/kg/day PO) has also been recommended to decrease the amount of urine crystals in equine urine.^190,191 Unfortunately, these ammonium salts are rather unpalatable and should be administered as two or three doses daily for effective urinary acidification. Further, the actual benefit of urinary acidification in horses has never been established, and recurrence may be more likely related to inadequate mucus secretion or persistence of damaged uroepithelium in the upper or lower tract. A more practical recommendation may be to administer 2 to 4 oz of salt in the feed daily to increase water consumption and urine flow. The increase in urine flow is accompanied by a decrease in urine pH to near-neutral values.

URETHRAL OBSTRUCTION

Calculi, neoplasms, congenital anomalies, and preputial edema and inflammation may all produce partial or complete obstruction of the urethra. Urethral calculi are most often calcium carbonate stones that lodge in the pelvic urethra in stallions or geldings,¹⁹² and the most common neoplasm causing urethral obstruction is squamous cell carcinoma of the penis.¹⁹³ Preputial edema and inflammation may develop as a consequence of trauma or parasitism (habronemiasis). In addition, overweight horses may develop recurrent preputial inflammation and infection associated with fat deposition in the sheath. Horses with the latter condition may fail to drop the penis during urination, and urine scalding within the sheath is likely a contributing factor to recurrent inflammation.

Complete urethral obstruction usually causes moderate to severe signs of colic, and an enlarged, turgid bladder is detected on rectal palpation. Careful palpation of the urethra below the anus may reveal the location of an obstructing urolith or frequent contraction of the urethralis muscle. Rarely, postrenal ARF may develop, or the bladder may rupture. Partial urethral obstruction is usually accompanied by dysuria, incontinence, and urine scalding of the hindlimbs. A diagnosis of urethral obstruction is based on clinical signs, rectal examination findings, external examination of the penis and prepuce, and passage of a catheter or endoscope through the urethra to the bladder.

Treatment of urethral obstruction usually involves surgery. Urethral calculi can be removed either by a subischial urethrotomy over the site of obstruction or by hydropulsion through the urethrotomy incision. Excessive tissue trauma should be avoided because it may increase the risk of urethral stricture and recurrent urolithiasis. Laboratory assessment of fluid and electrolyte status is important for correction of dehydration, azotemia, and electrolyte alterations that may develop with sweating (caused by pain), bladder rupture, or anuria. With squamous cell carcinoma, aggressive surgical resection of involved tissues is warranted with larger lesions, whereas smaller lesions may be amenable to treatment with 5-fluorouracil ointment. However, because recurrence rate of squamous cell carcinoma of the penis and prepuce is 20% or greater,¹⁹³ surgical removal should be initially considered in all affected horses. Detrusor function may be decreased if bladder distention had been ongoing for several days, and an indwelling bladder catheter (closed system) or treatment with bethanechol (0.25 to 0.75 mg/kg SC or PO every 8 to 12 hours) may help with recovery of detrusor function.

IDIOPATHIC RENAL HEMATURIA

HAROLD C. SCHOTT II

Idiopathic renal hematuria (IRH) is syndrome characterized by sudden onset of gross, often life-threatening hematuria.¹⁹⁴ Hemorrhage arises from one or both kidneys and is manifested by passage of large blood clots in urine. Endoscopic examination of the urethra and bladder usually reveals no abnormalities of these structures, but blood clots may be seen exiting one or both ureteral orifices. Although a definitive cause of renal hemorrhage may be established in some horses (e.g., renal adenocarcinoma, arteriovenous or arterioureteral fistula),^195,196 the disorder is termed idiopathic when a primary disease process cannot be found. Both genders, a wide age range, and several breeds of horses (including a mammoth donkey and a mule) have been affected. However, more than 50% of animals with IRH have been Arabians.

Use of the term idiopathic renal hematuria to describe this syndrome of horses was adopted from its use in human patients and dogs with severe renal hemorrhage.^197-201Benign essential hematuria and benign primary hematuria are other terms that have been used to describe less severe hematuria that is not associated with trauma or other obvious causes of hematuria. In humans and dogs, hematuria is more often a unilateral than a bilateral problem, similar to what has been observed in the few affected horses. The pathophysiology remains poorly understood, but macroscopic hematuria has been associated with immune-mediated glomerular damage (e.g., acute postinfectious glomerulonephritis, membranoproliferative glomerulonephritis, IgA nephropathy or Berger’s disease), thin basement membrane nephropathy, and the loin pain—hematuria syndrome in human patients.

Although hematuria and pigmenturia can accompany several systemic diseases in horses,^202-205 patients affected with IRH appear to have spontaneous, severe hematuria in the absence of other signs of disease. Although one report suggested that severe renal hemorrhage was caused by pyelonephritis,²⁰⁶ supportive data were lacking. In cases that I managed, neither UTI nor lithiasis has been detected, and the magnitude of hematuria often resulted in the need for repeated blood transfusions. As with hemorrhage associated with guttural pouch mycosis, the syndrome may produce episodic hemorrhage. Initially, hemorrhage is noted by finding a large amount of clotted blood in stall bedding or in the pasture. However, other client complaints (e.g., depression, anorexia, weight loss) are typically absent. Examination may reveal dried blood at the end of the penis or in the sheath of males or on the vulvar lips and between the hindlimbs of mares. In both genders, neoplasia of the external genitalia or urinary tract is an important differential diagnosis, and in mares, varicosities in the area of the vestibulovaginal sphincter also must be considered, especially in multiparous mares. When blood is not detected in the sheath or vulvar areas, further evaluation may be unrewarding because the renal bleeding may cease spontaneously. Bleeding has anecdotally been attributed to cystitis and pyelonephritis, in the absence of positive urine culture results, because hemorrhage stops during a course of antimicrobial therapy. More likely, spontaneous resolution has occurred. Further, the magnitude of hematuria is considerably greater with IRH than with most UTIs; pyuria is absent; and urine culture results are negative. In my experience, one or two initial episodes of hemorrhage are followed by a more severe hemorrhagic crisis within months to 2 years after observation of the initial bleeding episode. Of interest, renal colic has been notably absent in the history of affected horses.

Diagnosis

A diagnosis of IRH is made by exclusion of systemic disease, other causes of hematuria, and alterations in hemostasis. Physical examination may reveal tachycardia, tachypnea, and pale membranes consistent with acute blood loss. Rectal palpation may reveal an enlarged, irregular bladder resulting from the presence of blood clots. Azotemia is uncommon. Endoscopic examination is important to document that hematuria is originating from the upper urinary tract and to determine whether hemorrhage is unilateral or bilateral (Fig. 34-13). Repeated examinations may be required to answer the latter question. Ultrasonographic imaging is necessary to rule out nephrolithiasis or ureterolithiasis and may occasionally reveal a distended vascular space or renal vascular anomaly as the cause of hematuria. Renal scintigraphy can be a useful technique in affected horses, providing semiquantitative information about renal function when a nephrectomy is being considered. Renal biopsy and IF staining may assist in documenting immune-mediated glomerular injury, but the significance of such results is not well understood at this time.

Fig. 34-13 Cystoscopic image of a 19-year-old Arabian mare with idiopathic renal hematuria. A large blood clot can be seen exiting the left ureter, whereas the right ureteral opening appears normal.

URETHRAL HEMORRHAGE

HAROLD C. SCHOTT II

Although a recognized cause of hemospermia in stallions, defects or tears of the proximal urethra at the level of the ischial arch are a more recently described cause of hematuria in geldings.^207-209 Urethral defects typically result in hematuria at the end of urination, in association with urethral contraction. Affected horses generally void a normal volume of urine that is not discolored. At the end of urination, a series of urethral contractions results in squirts of bright-red blood. Occasionally, a smaller amount of darker blood may be passed at the start of urination. In most cases the condition does not appear painful or result in pollakiuria. Interestingly, the majority of affected stallions with hemospermia and geldings with hematuria have been quarter horses or quarter horse cross-breeds that have been free of other complaints.^210,211 Treatment with antibiotics for a suspected cystitis or urethritis has routinely been unsuccessful, although hematuria appears to resolve spontaneously in about 50% affected horses. Because the defects are difficult to detect without use of high-resolution videoendoscopic equipment, previous reports of urethral bleeding have been attributed to urethritis or hemorrhage from “varicosities” of the urethral vasculature. However, vasculature underlying the urethral mucosa becomes quite prominent when the urethra is distended with air during endoscopic examination, especially in the proximal urethra (to the point that blood can be seen flowing in the submucosal vasculature). Thus it would be logical to suspect that hemorrhage could arise from an apparent urethritis or urethral varicosity, although these problems are poorly documented in horses.

Examination of affected horses is often unremarkable, and laboratory analysis of blood reveals normal renal function, although mild anemia can be an occasional finding. Urine samples collected midstream or by bladder catheterization appear grossly normal. Urinalysis may have normal results, or an increased number of red blood cells (RBCs) may be found on sediment examination, a finding that would also result in a positive reagent strip result for blood. Bacterial culture of urine yields negative results. The diagnosis is made with endoscopic examination of the urethra, during which a lesion is typically seen along the dorsocaudal aspect of the urethra at the level of the ischial arch. External palpation of the urethra in this area is usually unremarkable but can assist in localizing the lesion because external digital palpation can be seen through the endoscope. With hematuria of several weeks’ duration, there is little evidence of inflammation; rather, the lesion appears as a fistula communicating with the vasculature of the corpus spongiosum penis (Fig. 34-14).

Fig. 34-14 Endoscopic image of the proximal urethra of a gelding with hematuria at the end of urination. A urethral defect can be seen between the arrows along the caudal aspect of the urethra as it passes dorsocranially over the pelvic brim.

Although the pathophysiology of this condition remains unclear, it has been speculated that the defect is the result of a “blowout” of the corpus spongiosum penis (cavernous vascular tissue surrounding the urethra) into the urethral lumen.²⁰⁹ Contraction of the bulbospongiosus muscle during ejaculation causes a dramatic increase in pressure in the corpus spongiosum penis, which is essentially a closed vascular space during ejaculation. The bulbospongiosus muscle also undergoes a series of contractions to empty the urethra of urine at the end of urination; thus the defect into the urethra may develop by a similar mechanism in geldings. Once the lesion has been created, it is maintained by bleeding at the end of each urination, and the surrounding mucosa heals by formation of a fistula into the vascular tissue. An explanation for the consistent location along the dorsocaudal aspect of the urethra at the level of the ischial arch has not been documented but may be related to the anatomy of the musculature supporting the base of the penis and an enlargement of the corpus spongiosum penis in this area. Further, a narrowing of the lumen at the distal extent of the ampullar portion of the urethra may also contribute to the location of the defects. An anatomic predisposition in quarter horses has not been documented but could be speculated based on an apparent increased risk in this breed.

Because hematuria may resolve spontaneously, no treatment may be initially required. If hematuria persists for more than a month or if significant anemia develops, a temporary subischial “incomplete” urethrotomy has been successful in some affected geldings. After sedation and epidural or local anesthesia, a catheter is placed in the urethra and a vertical incision made into the corpus spongiosum penis but not into the urethral lumen. The surgical wound requires several weeks to heal, and moderate hemorrhage from the corpus spongiosum penis is apparent for the first few days after surgery. Hematuria should resolve within a week after this procedure. Additional treatment consists of local wound care and prophylactic antibiotic treatment (typically a trimethoprim-sulfonamide combination) for 7 to 10 days.

POLYURIA AND POLYDIPSIA

HAROLD C. SCHOTT II

Polyuria and polydipsia (PU/PD) are defined as urine output in excess of 50 mL/kg/day and fluid intake of more than 100 mL/kg/day.^212,213 These values equate to production of 25 L of urine and consumption of 50 L of water for a 500-kg horse. It is important to remember that urine production and water consumption vary with age, diet, workload, environmental temperature, and GI water absorption.^214,215 For example, urine production increases by 50% to 100% when the diet is changed from a grass to a legume hay.²¹⁶ Similarly, horses in heavy exercise, stabled in hot climates, or with chronic diarrhea may have a water intake in excess of 100 L/day yet produce normal volumes of urine. The major causes of PU/PD in horses include renal failure (discussed previously), pituitary adenoma (Cushing’s disease), and primary or “psychogenic” polydipsia. Less common causes include excessive salt consumption, central and nephrogenic diabetes insipidus, diabetes mellitus, sepsis/endotoxemia, and iatrogenic causes (e.g., sedation with α₂-agonists, corticosteroid therapy, diuretic use).²¹³

POLYURIA/POLYDIPSIA WITH CUSHING’S DISEASE

Pituitary adenoma and the resulting syndrome of hyperadrenocorticism (Cushing’s disease) is common in older horses.²¹⁷ Although the most consistent clinical sign is hirsutism, PU/PD may be reported in some horses. For example, in one review of 17 horses with Cushing’s disease, PU/PD was found in 13 (76%).²¹⁸ However, in another series of 21 cases, PU/PD was not a historical complaint in any of the affected horses.²¹⁹ This discrepancy can be explained by the fact that PU/PD associated with Cushing’s disease is generally of lesser volume than that observed with psychogenic polydipsia or diabetes insipidus.

Cushing’s disease may lead to PU/PD by several mechanisms. First, polyuria may be the result of an osmotic diuresis. The renal threshold for glucose in horses (∼150 to 175 mg/dL) appears to be lower than in small animals.²²⁰ When plasma glucose concentration exceeds the renal threshold, the resultant glucosuria can lead to an osmotic diuresis. Although often implicated as the cause of PU/PD in horses with Cushing’s disease, glucosuria was found in only one of five affected horses in one report.²¹⁹ Further, horses with hyperglycemia and glucosuria may still be able to concentrate their urine in response to water deprivation.²²¹ A second mechanism implicated in the development of polyuria is antagonism of the action of antidiuretic hormone (ADH) on the collecting ducts by cortisol. Although frequently cited as the mechanism of polyuria in canine hyperadrenocorticism, experimental evidence to support this mechanism is lacking in both dogs and horses. Further, there is considerable species heterogeneity in the effects of corticoids on ADH activity, and in some species a primary dipsogenic effect may be more important. Next, growth of the adenoma may lead to impingement on the posterior pituitary and hypothalamic nuclei (located immediately dorsal to pituitary gland), the sites of ADH storage and production, respectively. Decreased ADH production and release would result in central diabetes insipidus as a third mechanism for polyuria.²¹⁷ Therefore, PU/PD seen in some, but not all, horses with pituitary adenomas is likely the combined result of several mechanisms.

PSYCHOGENIC POLYDIPSIA

Although rare, primary or “psychogenic” polydipsia is probably the most common cause of PU/PD in adult horses for which clients will have a primary complaint of excessive urination.^215,222 Horses with this problem are generally in good body condition and are not azotemic. Further, the magnitude of polyuria is typically dramatic, with owners reporting that horses drink two to three times more water than their stablemates, and stalls can be flooded with urine. In some horses, primary polydipsia appears to be a stable vice that reflects boredom, whereas in other cases it may develop after a change in environmental conditions, stabling, diet, or medication administration. Anecdotally, it has been reported to be more common in southern states during periods of high temperature and humidity.

The diagnosis of primary polydipsia is made by exclusion of renal failure and hyperadrenocorticism. In addition, other factors (e.g., salt supplementation, medication administration) must be excluded. Diabetes insipidus is excluded by demonstrating urinary concentrating ability after water deprivation.^223,224 Urine specific gravity should exceed 1.025 after water deprivation of sufficient duration (12 to 24 hours) to produce a 5% loss of body weight. In horses with long-standing polyuria, the osmotic gradient between the lumen of the collecting tubule and the medullary interstitium may be diminished (medullary washout). In these horses, ADH activity may not lead to an increase in urine specific gravity to values greater than 1.020. Consequently, in horses with primary polydipsia of several weeks’ duration that fail to concentrate their urine after 24 hours of water deprivation, a modified water deprivation test may be tried. This is performed by restricting water intake to approximately 40 mL/kg/day for 3 to 4 days. By the end of this period, urine specific gravity should exceed 1.025 in a horse that has had medullary washout. If urine specific gravity remains in the isosthenuric range (1.008 to 1.014), the polyuric horse should be further evaluated for early CRF in which urine concentrating ability may be compromised before the onset of significant azotemia. In theory, this could occur when two thirds to three fourths of functional nephrons have been lost. Subtle signs of decreased performance and mild weight loss would also support early renal failure.

Management of horses with primary polydipsia is empirical. Because this is a diagnosis of exclusion, once it has been established that the horse does not have significant renal disease, it is safe to consider restricting water intake to meet maintenance, work, and environmental requirements of the horse. In addition, steps should be taken to improve the attitude of the horse by reducing boredom. Increasing the amount of exercise and turning the horse out to pasture are possible options, along with providing a companion or diversions in the stall. Also, increasing the frequency of feedings or the amount of roughage in the diet may increase the time spent eating and thereby reduce the habitual drinking.

In an occasional case of primary polydipsia, PU/PD may be attributed to excessive salt consumption and is manifested by an increased fractional sodium clearance.²¹⁴ Such “psychogenic salt eaters” appear to be less common than “psychogenic water drinkers” because the former would have to consume a substantial amount of salt to develop polyuria. In fact, salt intake may have to exceed 5% to 10% of dry matter intake before PU/PD becomes apparent.^225,226 Successful management consists of limiting water intake and preventing access to excess salt.

DIABETES INSIPIDUS

Diabetes insipidus (DI) may occur because of inadequate secretion of ADH (neurogenic DI) or decreased sensitivity of the epithelial cells of the collecting ducts to circulating ADH (nephrogenic DI).^212,213,227 With both forms of DI, dramatic PU/PD may be reported, and affected animals fail to concentrate urine in the face of water deprivation.

In human patients, neurogenic DI is the more common form of DI, with both hereditary and acquired forms described.²²⁷ Two well-documented equine cases of neurogenic DI have been described.^228,229 Neither animal could concentrate urine in response to water deprivation, but administration of exogenous ADH resulted in an increase in urine specific gravity and decrease in urine volume. In a Welsh pony in which the condition was considered idiopathic, the absence of an increase in plasma ADH concentration after water deprivation further supported a diagnosis of neurogenic DI.²²⁸ Acquired neurogenic DI secondary to encephalitis was confirmed histologically in the other horse.²²⁹

Nephrogenic DI is most often a familial disorder in humans, with an X-linked semirecessive mode of inheritance.²²⁷ Therefore the disorder is carried by females and expressed in male offspring. Nephrogenic DI has been described in sibling thoroughbred colts, suggesting that an inherited form may also occur in horses.²³⁰ These colts could not increase urine specific gravity in response to water deprivation, although they did show appropriate increases in plasma ADH concentration. A lack of response to exogenous ADH administration further confirmed resistance of the collecting ducts to ADH. Nephrogenic DI can also develop in association with drug therapy or a variety of metabolic, infectious, or mechanical (postobstruction) disorders. Anomalous or neoplastic disorders resulting in structural deformation of the kidneys are other potential causes of nephrogenic DI.²²⁷

After determining that an equine patient with PU/PD is not azotemic, the initial diagnostic test to differentiate DI from primary polydipsia is a water deprivation test.^228,229 However, horses with suspected DI should be monitored closely during water deprivation because affected horses will continue to excrete excess water in the face of water deprivation. As a result, they may become substantially dehydrated (10% to 15%) within the first 12 hours of water deprivation. When a patient fails to concentrate urine during water deprivation, neurogenic DI can be differentiated from nephrogenic DI by measuring plasma ADH concentration or by administration of synthetic ADH (as illustrated by the cases previously described). Currently, equine ADH cannot be measured at commercial laboratories, but synthetic ADH (60 IU every 6 hours IM or SC) can be administered in combination with monitoring urine specific gravity.

Treatment of DI is directed at managing PU/PD. With neurogenic DI, hormone replacement therapy with desmopressin (dDAVP, a potent ADH analog administered as eyedrops) has been a successful treatment in small animal patients.²³¹ However, this treatment has not been described in horses and may be cost prohibitive. With nephrogenic DI, hormone replacement therapy is ineffective, and the only practical form of treatment for many years has been to restrict sodium and water intake and to administer thiazide diuretics. The latter treatment may reduce polyuria by 50% in human and canine patients.^227,232 Thiazide diuretics inhibit sodium reabsorption in the distal tubule (diluting segment of nephron) and increase solute delivery to the collecting duct, but the mechanism by which such therapy benefits patients with nephrogenic DI is not well understood. Administration of prostaglandin inhibitors or amiloride may also decrease polyuria in patients with nephrogenic DI. The former agents probably work by decreasing renal blood flow and GFR, whereas amiloride, a sodium channel blocker, is thought to act similar to the thiazide diuretics.²¹⁶ No reports have documented the use of these treatments in horses.

DIABETES MELLITUS

Diabetes mellitus (DM) is a state of chronic hyperglycemia usually accompanied by glucosuria. The resultant osmotic diuresis is an occasional cause of PU/PD in horses and was described to result in a water intake in excess of 80 L/day in one report.²³³ Type 1, or insulin-dependent, DM results from of a lack of insulin, which in human patients is usually attributable to viral or autoimmune disease. Individuals with type 2, or non-insulin-dependent, DM have normal to high insulin concentrations, but their tissues are insulin insensitive. The most common cause of equine type 2 DM is Cushing’s disease, in which elevated plasma cortisol concentration appears to antagonize the effects of insulin. Although uncommon, there are a few reports of both type 1 and type 2 DM that were not caused by a pituitary adenoma and that resulted in PU/PD as one of the presenting complaints.^233-235

SEPSIS/ENDOTOXEMIA

Polyuria and polydipsia have been described in horses with sepsis or endotoxemia, although other clinical signs (e.g., fever, abdominal pain, weight loss) predominate.²³⁶ The mechanism of PU/PD is unclear but may result from endotoxin-induced prostaglandin production. Prostaglandin E₂ (PGE₂) is a potent renal vasodilating agent that can antagonize the effects of ADH on the collecting ducts.²³⁷ Some horses with chronic gram-negative bacterial infections (e.g., peritonitis, pleuritis) may have low-grade or intermittent endotoxemia as a mechanism for PU/PD, similar to the polyuria observed with canine pyometra.²³⁸

IATROGENIC POLYURIA

A final cause of PU/PD may be iatrogenic as a result of several treatments. The most obvious iatrogenic cause is fluid therapy, for which polyuria is a desired response. Polyuria has also been observed with exogenous corticosteroid administration, although the mechanism remains unclear. Humans and dogs appear to experience a potent thirst response to exogenous corticosteroids; thus, polydipsia may be an important cause of the polyuria observed. In horses receiving chronic dexamethasone treatment for immune-mediated disorders, profound glucosuria (2 to 3 g/dL) may be observed and could lead to an osmotic diuresis. Finally, a transient diuresis or polyuria accompanies sedation with the α₂-agonists xylazine and detomidine.²³⁹ Although these agents also cause transient hyperglycemia and occasional glucosuria, a more likely mechanism for the polyuria is existence of α₂-adrenoreceptors on collecting-duct epithelial cells. Activation of these receptors is another mechanism by which the action of ADH can be antagonized.²⁴⁰

RENAL TUBULAR ACIDOSIS

MONICA ALEMAN

Renal tubular acidosis (RTA) is a syndrome characterized by abnormal renal tubular function, which results in a hyperchloremic metabolic acidosis.^241-243 Hyperchloremia develops as a result of enhanced renal conservation of chloride consequent to bicarbonate loss. RTA can be categorized as primary (genetic or idiopathic) or secondary when attributed to an underlying disease process or drug administration. Drug-induced RTA has been documented in human patients after administration of amphotericin B, trimethoprim-sulfamethoxazole, outdated tetracyclines, gentamicin, cephalosporins, carbonic anhydrase inhibitors, lithium carbonate, and other organic compounds.

Three types of RTA have been described: I (distal), II (proximal), and IV (hyperkalemic distal).^241-243 Types I and II have been reported in dogs, cats, and horses. Type I develops when distal tubular excretion of hydrogen ions (H⁺) becomes compromised, and affected patients are unable to produce acidic urine. Type II results from decreased proximal tubular bicarbonate resorption and subsequent loss of bicarbonate in the urine. Because H⁺ ions are normally excreted as bicarbonate is reabsorbed in proximal tubules, acidosis with both type I and type II RTA results from decreased H⁺ excretion. Type II RTA often is a self-limiting problem but may be accompanied by more widespread proximal tubular dysfunction, leading to defective resorption of glucose, amino acids, phosphate, potassium, sodium, calcium, magnesium, uric acid, and other organic acids. The latter disorder is known as Fanconi’s syndrome; as with RTA, it may be a primary (inherited) problem or can develop secondary to kidney, metabolic, and autoimmune diseases or drug administration.^241-243 Although there are no well-documented reports, Fanconi’s syndrome likely develops in an occasional horse as a sequela to nephrotoxic or vasomotor ARF. To date, type IV, or hyperkalemic distal, RTA has only been described in human patients.²⁴²

Renal tubular acidosis is a sporadically occurring metabolic disorder in horses.^244-247 There is no obvious breed or gender predilection, and to date, no evidence indicates that RTA is an inherited condition in horses. Typically, affected horses present with profound depression and anorexia and may have a history of poor performance, weight loss, and signs of abdominal pain. Vital parameters are generally within normal ranges, and horses do not appear clinically dehydrated. Hematologic and clinical chemistry findings are usually within reference ranges, with the exception of electrolyte concentrations and acid-base balance. A profound metabolic acidosis (plasma bicarbonate concentration <13 mEq/L and venous blood pH <7.25) and hyperchloremia (serum chloride concentration = 105 to 120 mEq/L) are characteristic for horses with RTA. A compensatory decrease in carbon dioxide partial pressure (PCO₂) is also observed in most horses with RTA. Hypokalemia (and total body potassium depletion) may occur in horses with RTA because of the combined effects of anorexia and ongoing loss of potassium in urine, especially in patients with type II RTA, in which bicarbonaturia further increases urinary potassium excretion.

Mild to moderate azotemia may be detected in horses with RTA, especially when they are dehydrated at presentation. Affected horses may also have evidence of renal tubular damage detected on urinalysis (e.g., pigmenturia, glucosuria, abnormal sediment), and urine specific gravity may be low. Despite profound metabolic acidosis, urine pH is generally neutral to alkaline. If pursued, renal biopsy results generally support tubulointerstitial disease (CIN).

Differentiation of type I from type II RTA in human and canine patients is most easily accomplished by assessing urine pH; it remains neutral to alkaline with type I and should be neutral to acidic with type II.^241-243 Most horses with RTA have had neutral to alkaline urine; however, because herbivores normally have alkaline urine, this distinction may be less useful in horses with RTA. A few reports have described horses with acidic urine,^246,248,249 supporting type II RTA, but urine pH values near neutral are difficult to interpret. Assessment of all laboratory abnormalities (Table 34-1), along with additional testing (e.g., ammonium chloride challenge, urinary ammonium concentration) may allow further discrimination between type I and type II RTA.^249,250 However, this distinction may not be entirely necessary because the approach to treatment and the prognosis are similar for both types of RTA in horses.

Table 34-1 Classification of Type I and Type II Renal Tubular Acidosis

Treatment of RTA consists primarily of IV and oral administration of sodium bicarbonate. Response to treatment appears to be largely dependent on the rate of NaHCO₃ administration. For initial correction of acidosis, IV NaHCO₃ must be administered aggressively, and large amounts (3000 to 9000 mEq) are often required to return plasma bicarbonate concentration to values above 20 mEq/L. Half the estimated bicarbonate deficit is generally replaced with IV NaHCO₃ over 6 to 12 hours, and the remaining deficit is replaced with a combination of IV and oral NaHCO₃ (initial oral dose: 100 to 150 g twice daily; 1 g contains ∼12 mEq NaHCO₃). Close monitoring of serum electrolyte concentrations and acid-base balance is required to adjust the rate of IV NaHCO₃ replacement. Marked improvement in attitude and appetite usually accompanies correction of the acidosis, but unfortunately, relapse after discontinuation of IV therapy can occur. Continued oral administration of NaHCO₃ (baking soda) for months to years may be required for maintenance of a normal acid-base status in individual horses.

Because potassium excretion is proportional to the bicarbonate delivery to the distal tubule, initial correction of acidosis with NaHCO₃ promotes kaliuresis and may exacerbate potassium depletion, especially when horses have been anorectic for several days. Therefore, concurrent supplementation with IV or oral potassium chloride is usually also necessary during initial correction of the acidosis. Complications associated with rapid correction of acidosis have not been described, but transient diarrhea may develop if large quantities of NaHCO₃ (>200 g) are given by nasogastric tube to horses that are completely anorectic.

Recurrence of metabolic acidosis also can occur when oral NaHCO₃ is discontinued. Relapses can be immediate or delayed for weeks to months, especially in horses that have RTA with evidence of renal damage. Reinstitution of NaHCO₃ supplementation usually corrects the metabolic abnormalities and accompanying depression and anorexia. The short-term prognosis for horses with RTA is good, and although the long-term prognosis has not been well documented, several horses have been reported to recover completely.^244-246

BLADDER RUPTURE IN ADULT HORSES

THOMAS J. DIVERS

On rare occasions, bladder rupture may occur in adult horses. The problem often develops in association with urethral obstruction, foaling, or prolonged recumbency.²⁵¹ As azotemia develops, affected horses become depressed and inappetent. Clinical signs may not be apparent for several days, or stranguria may be observed, depending on the cause of the rupture. Abdominal distention is not as apparent in adult horses as in foals.

The diagnosis is based on history, rectal examination findings, laboratory results, and findings on ultrasonographic or cystoscopic examination. Postrenal azotemia develops within 24 hours after rupture and is accompanied by hyponatremia and hypochloremia. Unlike uroperitoneum in neonates, hyperkalemia is not a consistent finding. Transabdominal ultrasonographic examination of the abdomen reveals a large amount of peritoneal fluid (Fig. 34-15); abdominal fluid is easily recovered on abdominocentesis, and peritoneal fluid creatinine is twofold or greater than that of serum. Detection of calcium carbonate crystals on cytologic examination of peritoneal fluid is also diagnostic for uroperitoneum. Endoscopic examination of the bladder should allow determination of the location and extent of the bladder tear. Rarely, uroperitoneum may also develop in some horses without full-thickness disruption of the bladder wall, and it is difficult to establish definitively the cause of uroperitoneum in these cases.

Fig. 34-15 Transabdominal ultrasonographic image of the right inguinal area of an adult horse with a ruptured bladder. A large amount of free hypoechoic fluid is apparent.

Surgical repair is indicated in horses with large tears in the ventral half of the bladder. In patients with small dorsal tears or incomplete tears, use of an indwelling bladder catheter (closed system) to keep the bladder small may allow the tear to heal without surgery.²⁵² Before surgery, IV fluids should be administered to correct dehydration, along with broad-spectrum antibiotics as prophylaxis against sepsis. If the abdomen is distended, urine accumulated in the abdomen should be removed (e.g., by placement of chest tube or other large catheter through ventral abdominal wall) before anesthesia is induced, to avoid further compromising respiration.

URINARY SYSTEM DISORDERS IN THE FOAL

THOMAS J. DIVERS

Umbilical disorders of the neonatal foal, including patent urachus, urachal infections, and omphalitis, are discussed in Chapter 19.

UROPERITONEUM

Bladder Rupture

The most common disorder of the bladder of otherwise healthy newborn foals is bladder rupture.^253-255 It is more common in colts, and clinical signs include repeated posturing to urinate and stranguria during the first 2 days of life. As urine accumulates in the abdomen, depression and abdominal distention typically develop between days 2 and 4. Repeated posturing and stranguria can easily be misinterpreted as tenesmus associated with meconium impaction (Fig. 34-16). Further, affected colts may continue to void small volumes of urine. Thus, establishing a diagnosis of a ruptured bladder can initially be challenging until more obvious signs of uroperitoneum (e.g., decreased nursing, abdominal distention) develop.

Fig. 34-16 A 2-day-old foal exhibiting stranguria caused by a ruptured bladder. Note the caudal position of the hindlegs, suggesting that the foal is straining to urinate rather than defecate. Differentiating between stranguria and tenesmus (meconium impaction) is not always easy.

Laboratory findings in foals with uroperitoneum include hyponatremia, hypochloremia, hyperkalemia, and azotemia.^253-256 An occasional foal may also develop intermittent fine muscle tremors or a cardiac arrhythmia resulting from these electrolyte alterations, especially hyperkalemia. Transabdominal ultrasonographic examination usually reveals a large quantity of free fluid in the abdominal cavity, and peritoneal fluid creatinine/serum creatinine ratio greater than 2:1 confirms uroperitoneum.^253-256

Treatment of bladder rupture includes surgical closure of the defect, supportive care, and broad-spectrum prophylactic antibiotics for 3 to 7 days postoperatively.^{253,254,256,257} An emergency surgical procedure is usually not required, and in most cases, surgery should be postponed for several hours until electrolyte abnormalities are partially corrected (most notably correction of hyperkalemia to a serum concentration <6.0 mEq/L). This can usually be accomplished by IV administration of 1 to 3 L of a 0.9% NaCl/5% glucose solution. Treatment with insulin should be avoided unless hyperkalemia is causing significant electrocardiographic (ECG) abnormalities and response to initial fluid therapy is poor. With marked hyperkalemia or abdominal distention causing respiratory embarrassment, slow drainage of urine from the abdomen (e.g., by chest tube or similar catheter) may be necessary before induction of anesthesia. Despite significant azotemia in some affected foals, use of aminoglycoside antibiotics is generally safe because the azotemia is postrenal rather than reflecting intrinsic renal disease. In most cases, placement of a urinary catheter to maintain an empty bladder for the initial 2 postoperative days is not necessary. However, uroperitoneum may recur after surgery in an occasional foal as a result of ongoing leakage from the bladder tear. When this complication occurs, it can usually be managed conservatively by placement of an indwelling bladder catheter (closed system) for 3 to 5 days. Rarely, a second celiotomy may be required.

CYSTITIS

Cystitis is rare in foals but can develop in recumbent premature or neonatal foals being treated with broad-spectrum antibiotics. Voided urine may have a characteristic flocculent consistency. When cystitis is suspected, the bladder should be catheterized and a urine sample submitted for urinalysis and quantitative culture. UTIs with Candida species are fairly common in recumbent neonates. Specific antimicrobial therapy is not usually necessary for Candida cystitis as long as systemic antibiotics can be discontinued. If antibiotic therapy continues, dissemination of the yeast infection can spread to other sites (e.g., joints).

SERUM CREATININE ELEVATIONS IN NEWBORN FOALS

During the first 1 to 3 days of life, creatinine concentration in newborn foals is often 30% to 40% higher than in their dams.²⁶⁶ The cause is unclear but likely related to an inability of creatinine to equilibrate rapidly across placental membranes. As supportive evidence, creatinine concentration of normal amniotic fluid (that contains fetal urine) at term is approximately 10 mg/dL (and may exceed 30 mg/dL in some mares).²⁶⁷ This transient increase in creatinine, which may occasionally exceed 20 mg/dL in premature foals, has been called a “spurious” elevation, but this term should be discontinued because creatinine is truly increased. When an elevated creatinine level is detected in an otherwise healthy foal (that has also been observed to urinate normally), there may be no cause for alarm. However, if creatinine does not decline rapidly after birth or remains greater than 2.5 mg/dL on day 3 of life, peritoneal or retroperitoneal accumulation of urine, renal hypoplasia, or other causes of renal failure should be considered. Unlike creatinine, BUN values in foals are typically low (<10 mg/dL) after day 2 and remain low for the first several months of life. This finding can be attributed to the anabolic state of the growing foal.

Urinalysis results in normal neonatal foals are also different from those in adult horses. Specifically, normal foals may have marked proteinuria for 1 to 2 days after birth resulting from filtration of small—molecular-weight proteins absorbed with colostrum. Next, water intake on a predominantly milk diet (∼250 mL/kg/day, compared with intake of 50 mL/kg/day of water by adults) is high in foals. As a result, after day 2 of life, urine is hyposthenuric (specific gravity, 1.002 to 1.006) and remains that way for several months. Finally, urinary enzyme activity and sodium and chloride clearances may be greater than adult values, and urine pH is neutral to acidic in foals.²⁶⁸

ACUTE RENAL FAILURE

Acute tubular necrosis is the most common pathologic lesion causing ARF in neonatal foals. Many cases develop during or after episodes of diarrhea, likely caused by poor perfusion (vasomotor nephropathy). Surprisingly, the diarrheal disease in some affected foals does not appear to be serious, but they may develop ARF. Similar to adult horses with ARF, the prominent clinical signs are depression and development of edema. Abnormal laboratory findings include azotemia, hyponatremia, hypochloremia, and hypocalcemia. Foals are more likely to develop significant hyperkalemia and hyperphosphatemia than adult horses with ARF. A urine specific gravity less than 1.018 and microscopic hematuria are usually also found in foals with ARF. Urine output of sick neonates should be monitored closely because they may become oliguric to anuric 12 to 24 hours before significant depression or azotemia is recognized. In addition, fluid retention during incipient ARF is another cause of inappropriate weight gain (e.g., >2 kg in 24 hours), which can often be detected before obvious edema develops.

Nephrotoxicity, most often from administration of aminoglycoside antibiotics or tetracycline, is another important cause of ARF (usually nonoliguric) in neonatal foals. As in adult horses, the recent change to once-daily aminoglycoside dosing appears to have decreased the incidence of hospital-acquired ARF in foals. However, it is important to remember that sick neonates are often more critically ill than many adult horses treated with aminoglycosides. Premature foals appear to be at even greater risk of nephrotoxicity than term foals. Judicious fluid therapy to correct dehydration and maintain blood pressure is an important precaution. Although there is a general impression that amikacin may be less nephrotoxic than gentamicin in foals, little supportive data exist. Regardless of which aminoglycoside antibiotic is selected, monitoring trough concentrations (<2 mg/mL for gentamicin; <4 mg/mL for amikacin) is warranted to decrease the risk of aminoglycoside toxicity in high-risk neonates. Dosage adjustment may be necessary in seriously ill neonates or premature foals because renal clearance may be decreased.²⁶⁹

The principles of treatment of ARF in neonates are essentially the same as those for adult horses (see earlier discussion). However, greater attention must be paid to monitoring responses to fluid therapy, including twice-daily measurement of body weight. Although foals that have a bout of ARF in the neonatal period would seem at greater risk of developing CRF later in life, no long-term follow-up study has corroborated this speculation.

SEPTIC RENAL DISEASE IN FOALS

Multifocal renal abscesses or infarct may be a complication of neonatal septicemia and can lead to ARF. Actinobacillus equili is the most common pathogen causing renal abscesses, but affected foals often die or are euthanatized because of overwhelming sepsis before clinical signs of ARF develop. Foals 2 to 4 days of age appear to be at greatest risk of developing acute Actinobacillus septicemia; when this problem is suspected, IV therapy with penicillin and gentamicin (at prolonged dosage) is recommended (see Chapters 18 and 20).

RUMINANT RENAL SYSTEM

ULCERATIVE POSTHITIS AND VULVITIS

DAVID C. VAN METRE

Ulcerative posthitis and vulvitis (enzootic balanoposthitis, pizzle rot, sheath rot) is an ulcerative bacterial infection of the mucous membrane and surrounding skin of the prepuce and vulva of small ruminants. The causative organism, Corynebacterium renale, inhabits the mucosal surface of the prepuce and vulva in low numbers. It proliferates and induces disease under conditions of high urea concentration in urine, which typically result from excessive dietary protein content. Losses result from debilitation caused by pain, incapacitation of breeding animals, loss of breeding soundness, and deformation of external genitalia. Venereal spread is possible.

Clinical Signs

In rams, bucks, and wethers the infection begins as a moist ulcer, usually at or near the mucocutaneous junction of the prepuce. The ulcer surface is soon covered with a thin, loose, brown to red, malodorous scab (Fig. 34-17). If the scabs are removed, little or no hemorrhage will occur from the underlying tissue.¹ Focal swelling is often noticeable at the cranial aspect of the prepuce, and the area is usually painful on palpation.

Fig. 34-17 Ulcerative posthitis in a Suffolk ram.

If unchecked, the infection may spread along the mucosal surface inside the prepuce, creating the more serious internal form of ulcerative posthitis. In such cases the entire prepuce may be swollen and elongated. Affected animals often show dysuria, and goats may vocalize during voiding. Weight loss may occur in chronic cases. As local inflammation progresses, ulceration of mucosal surfaces may result in fibrous adhesions between the penis and prepuce. Severe inflammation of the glans penis may cause stricture of the urethral process (pizzle) and restriction of urine egress. Impairment of breeding soundness may result from admixing of blood or exudate into the ejaculate, penile adhesions, cicatricial scarring of the preputial orifice, or suppurative urethritis; pain may limit libido as well.

Ulcerative lesions of similar appearance can develop on the vulva and perineum of affected ewes and does. Gross vulvar enlargement may be noticed from a distance. Dysuria may result from involvement of the urethral orifice. The fibrosis and contracture that develop in chronic, severe cases may distort normal vulvar conformation to the point of impairing copulation or partuition.

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Differential Diagnosis

Ulcerative dermatosis (lip and leg ulcer) is a dermatitis of sheep caused by an unclassified poxvirus related to the parapox virus of contagious ecthyma.² Infection with this agent may manifest as balanoposthitis and vulvitis, and the crusted ulcers that develop closely resemble those induced by infection with C. renale. Removal of the crusts overlying ulcerative dermatosis lesions may reveal a granular lesion that bleeds readily. The genital form of ulcerative dermatosis occurs most often in the fall breeding season in the western United States. Ulcers on the lips, nares, coronets, and interdigital spaces may also be present.² Contagious ecthyma (orf) occasionally affects the genitalia and perineum, although lesions are much more frequently found on the lips, face, and udder. These lesions are raised, appear proliferative, and are covered with a thick, durable scab. Urolithiasis must be considered strongly in the differential diagnosis of any dysuric male or castrated male small ruminant. Although rare in small ruminants, preputial trauma, particularly if resulting from entrapped grass awns, can cause preputial swelling, pain, and exudation within the preputial cavity. External ulcerative lesions would not be expected in such cases.

Caprine herpesvirus 1 (CHV-1) was isolated from aborted fetuses in three separate California goat herds.⁶ A buck on the premises had shallow, red, irregularly shaped ulcers in its prepuce that tested positive for CHV-1 on polymerase chain reaction (PCR). Biopsy of the ulcers revealed intranuclear inclusion bodies within the stratum spinosum of the preputial epithelium.

Pathophysiology

C. renale is an aerobic, gram-positive, pleomorphic, club-shaped bacterium that is a normal inhabitant of the skin and external genitalia of small ruminants.^3,4 This organism is capable of surviving in wool and scabs from lesions for as long as 6 months and can survive freezing temperatures in lesion exudate.⁵C. renale is capable of hydrolyzing urea. Experimental diversion of urine flow has demonstrated that the presence of urine is required for both induction of and maintenance of lesions on the genitalia.³ The organism proliferates on the genital mucosal surface in response to elevated urinary concentration of urea. Diets high in crude protein or nonprotein nitrogen increase the urinary urea content and are required for development of the disease.^1,5C. renale hydrolyzes urea to ammonia, which causes ulceration of the prepuce and surrounding skin.

Epidemiology

This condition appears to be more common in males and wethers than in females.¹ Lambs under 6 months of age can occasionally be affected,⁵ but given the relatively short lifespan of market lambs, the disease is most often recognized in rams, Angora wethers, and pet wethers. Although all breeds are susceptible, higher rates of this disease are found in Merinos and Angoras.^1,7 Because of the dense wool and hair coat of these breeds, urine soaking near the preputial orifice may increase the local concentration of urea. Seasonal differences in the incidence of the disease are thought to reflect shearing schedules and changes in the availability of high-protein diets.¹

Because the organism is part of the normal skin and genital flora, disease can occur in isolated individuals under proper dietary conditions. However, the disease is contagious, because transfer of necrotic debris from the ulcers of affected animals can induce the disease in normal animals.^1,5 Venereal transmission of the disease has been documented. Several months may pass between the exposure of ewes to infected rams and the development of vulvitis in ewes.⁵

Treatment and Prevention

Affected animals should be isolated to limit venereal or contact transmission. Wool or hair should be removed from the skin surrounding the prepuce or vulva, and a topical antibiotic may be applied. Caustic antiseptic solutions should not be used. Treatment with systemic antibiotics is indicated for advanced cases or for outbreaks, in which handling of several animals for topical therapy is not feasible. Penicillin is the antibiotic of choice, although tetracycline has provided favorable results. Treatment should continue until the lesions have dried and acute inflammation has subsided.

Reduction of protein and nonprotein nitrogen intake is crucial for successful treatment of affected animals and for prevention of additional cases.^1,5 Dietary crude protein levels of 16% to 18% (or higher) predispose sheep and goats to ulcerative posthitis and vulvitis.¹ Reduction of dietary protein alone may result in satisfactory cure if the lesions are early in development. Shearing, especially at the time of highest protein intake, may be efficacious in reducing disease incidence.⁵ Incorporation of grass hay feeding into a program of legume pasture grazing may help limit protein intake.

Surgical treatment of advanced cases has been described.⁸ The procedure involves resection of ventral preputial tissue to allow for normal urine flow and, less often, successful return to breeding.

Prognosis

Response to treatment is optimal early in the infection, before deformation of the prepuce and vulva as a result of fibrosis. The chances for full recovery without recrudescence are poor if dietary protein intake is not reduced. Complete recovery of breeding soundness is unlikely in animals with internal ulcerative posthitis.

UROLITHIASIS

JENNIFER M. MACLEAY

Urolithiasis is a common metabolic disease occurring in most mammalian species. Uroliths cause disease through trauma to the urinary tract and obstruction of urinary outflow. Calculi (uroliths) most often lodge in the urethra, although obstruction of the bladder trigone, ureters, or renal pelvis can also occur. Sequelae to urinary tract obstruction include urethral perforation and rupture, urethral stricture, bladder rupture, ureteral rupture, hydroureter, hydronephrosis, and rarely, rupture of the kidney(s). Urolithiasis can occur in outbreaks or as an endemic problem in group-housed animals or as an individual disorder in animals kept as pets. A definitive diagnosis of urolithiasis in a single animal suggests that all males in the population are at risk for the disease, because of the importance of dietary and environmental factors in its pathogenesis.⁹

HISTORICAL FINDINGS

The clinical signs of urolithiasis can vary; duration, extent (complete vs. partial), and location of the obstruction determine the historical and examination findings. The early clinical signs can be remarkably subtle and may include anorexia, depression, and mild bloat. A history of colic and straining to urinate or defecate may be provided, and novice owners often mistake stranguria for constipation or tenesmus. To aid in the diagnosis, suspected cases can be placed in a dry, unbedded stall to allow for assessment of urine output.

Acute Urethral Obstruction

Clinical Findings

Impacted calculi lead to urethral trauma and progressive bladder distention, resulting in strangury and abdominal pain. Affected animals may be restless, tread, swish their tails, and or grind their teeth. Goats and camelids may vocalize. Stranguria is manifested as repetitive bouts of stretching and contraction of the abdominal muscles. Straining may induce secondary rectal prolapse; therefore, urethral obstruction should be investigated as the primary disease in cases of rectal prolapse. Rarely, affected calves develop a visible dilation of the urethra at the midline of the perineum proximal to the obstruction.¹⁰ Tachycardia, tachypnea, and mild bloat secondary to ruminal stasis are more common findings. Anuria occurs if urethral obstruction is complete, whereas urine may dribble in cases of partial obstruction. If a urine sample can be collected for dipstick analysis, proteinuria and occult hematuria are frequently detected. Crystals or blood may be found on the hairs of the preputial tuft; in cases of anuria the hairs are dry. Fever is usually absent.

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The lumen of the bovine urethra narrows at the distal aspect of the sigmoid flexure, near the level of insertion of the retractor penis muscles.^11,12 Calculi most frequently become lodged at this site in cattle,^11-14 and pain or focal swelling over this area may be appreciated. Rectal examination (digital rectal examination in small ruminants) often reveals pulsation of the pelvic urethra. In cattle, bladder distention is palpable rectally except in cases of complete obstruction complicated by rupture of the urethra or bladder.

Abdominal palpation is useful in affected small ruminants, small camelids, and pot-bellied pigs. The examiner should place the fingertips of each hand into the ventral flank on each side of the abdomen. While slowly pressing the fingertips toward midline in the caudal abdomen, the examiner may encounter an orange- to grapefruit-sized, firm, spherical structure, which is the distended bladder (Fig. 34-18). Severe bladder distention will not be palpated in cases of incomplete urethral obstruction or bladder rupture.

Fig. 34-18 Palpation of the bladder of a Barbados wether.

The urethral process (pizzle) is the most common site of calculus impaction in sheep and goats and should be examined in suspected cases of urolithiasis.^14,15 Sedation or general anesthesia facilitates extrusion of the penis for examination. Because of its diuretic effect, xylazine may exacerbate bladder distention and is not recommended. Diazepam (0.1 mg/kg IV slowly) or acepromazine (0.05 to 0.1 mg/kg IV or IM) have been used successfully, either as sole agents or in combination with butorphanol (0.05 to 0.1 mg/kg IV). Alternatively, in hemodynamically stable individuals, it is possible to induce light general anesthesia with isoflurane.

An adjunct or alternative to sedation is administration of epidural anesthesia, which provides greater patient comfort and eliminates muscular resistance to penile extrusion. One milliliter of 2% lidocaine per 5 kg of body weight is injected into the epidural space at the lumbosacral junction.¹⁶ Lower dosages may provide sufficient anesthesia. The total dose should not exceed 15 mL of 2% lidocaine in any small ruminant, regardless of size.¹⁶ If cerebrospinal fluid (CSF) is obtained, one half of the epidural lidocaine dosage can be administered as a true spinal block. Hindlimb motor blockade, potentially lasting for several hours, is expected with either epidural or true spinal anesthesia at this site.

To exteriorize the penis, the sheep or goat is propped up on its rump. The examiner can then exteriorize the penis by pushing the sigmoid flexure cranially from the base of the scrotum while pulling the sheath caudally. Small towel clamps or Allis tissue forceps can be used to apply traction to the penis. In many cases, preputial mucosa must be carefully grasped and extruded before the penis can be reached with a second pair of forceps. The urethral process can then be inspected and palpated for the presence of discrete uroliths or sandlike grit within the lumen. If the urethral process is obstructed, it can be amputated with scissors or a scalpel blade (see Surgical Treatment).

Differential Diagnosis

Tachycardia, colic, bloat, and anorexia are characteristic of gastrointestinal (GI) obstruction, but auscultation and percussion of the abdomen, abdominal succussion, rectal examination, and abdominal ultrasonographic examination should differentiate this condition from acute urethral obstruction. Goats with grain overload will occasionally vocalize and show signs of colic.¹⁷ Encephalopathies, salmonellosis, coccidiosis, and proctitis from rectal prolapse or trauma frequently cause tenesmus. Additional signs of primary neurologic or GI dysfunction should be evident with these diseases.

Although rare in male ruminants, primary urinary tract infection (UTI) may result in dysuria and pollakiuria. Bladder distention is uncommon with UTI, and large numbers of white blood cells (WBCs) and bacteria are present in the urine sediment. Occasionally an animal with urolithiasis successfully voids the obstructing urolith(s). The resultant traumatic urethritis might cause dysuria, but the rate and ease of urination typically improve over time and with antiinflammatory treatment.

In younger animals, it is important to consider congenital abnormalities, such as ectopic ureter(s), pelvic displacement of the urinary bladder, and urethral duplication. Congenital abnormalities may be manifest at birth or not until later, depending on the level of observation and whether the defect results in obstruction, partial obstruction, or constant urine dribbling.

Urethral Rupture

Urethral rupture is a common complication of urethral obstruction in cattle. The wall of the obstructed urethra undergoes pressure necrosis, causing leakage of urine into the subcutaneous tissue of the perineum and ventral abdomen. Sequelae include cellulitis, penile adhesions (possibly creating phimosis), and urethral stricture. Erection failure secondary to vascular obstruction of the corpus cavernosum of the penis has been reported as a sequela to urethral obstruction and rupture in a goat.¹⁸

Clinical Findings

Affected animals are frequently depressed and inappetent and have bilaterally symmetric, pitting edema in the ventral perineum, inguinal region, prepuce, and ventral abdomen (Fig. 34-19). Swelling of the abdominal wall may extend as far forward as the axillae. The affected areas are initially warm and painful on palpation. As necrosis progresses, the tissues become cool, dark, nonpainful, and potentially gangrenous. A fistula may develop to allow urine to escape. Fever may occur if tissue necrosis and sloughing are extensive. Rectal examination in steers and bulls reveals a small bladder.

Fig. 34-19 Urethral rupture in a Holstein steer. Tissue swelling from urine accumulation may extend to the sternum and axillae.

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Differential Diagnosis

Ventral abdominal swelling is found with umbilical or scrotal hernias with or without concurrent subcutaneous infection. These conditions can be differentiated from urethral rupture by careful palpation of affected tissues and through ultrasonography to identify defects in the body wall or presence of bowel in the swelling. Pain and heat are more pronounced in local infection than in urethral rupture. Aspiration of subcutaneous fluid with cytologic examination is helpful in identifying primary infectious processes. In bulls, penile hematomas may cause localized swelling of the prepuce in the prescrotal region and caudal sheath; unlike urethral rupture, however, the swelling does not involve the ventral abdominal wall. Aspiration of a suspected penile hematoma is not recommended because of the risk of iatrogenic infection.

Chronic Partial Urethral Obstruction

An uncommon form of urolithiasis, chronic partial urethral obstruction occurs if calculi impair but do not completely obstruct urine outflow.²⁴ Chronic retention of urine elevates fluid pressure within the urinary tract lumen, potentially leading to hypertrophy of the bladder wall, hydroureter, and hydronephrosis. Azotemia, progressive renal failure, and uremia are evident in cases that develop hydronephrosis.

Clinical Findings

Affected animals have been termed “dribblers” because of their characteristic slow or intermittent urine flow during voiding.²⁵ Lethargy, reduced appetite, and thin body condition are evident if renal failure has developed. On rectal examination the bladder may be small, and thickening of the bladder wall may be palpable.²⁴

Differential Diagnosis

Urine dribbling may also occur in animals with neurologic disease caused by previous urethral trauma (stricture formation), congenital anomalies of the urogenital tract, chronic infection, or neoplasia. Contrast urethrography may be used to identify the presence of strictures or anomalous structures. Small ruminants with the internal form of ulcerative posthitis may dribble urine. In such cases, characteristic preputial lesions are present. Tumors of the urinary tract, although rare compared to urolithiasis, may cause gradual obstruction in cattle, small ruminants, and camelids.

Ureterolithiasis and Nephrolithiasis

CLINICAL PATHOLOGY

PREOPERATIVE CONSIDERATIONS

Ruminants and camelids with urinary tract obstruction, particularly those with uroperitoneum, often require preoperative stabilization of hypovolemia and correction of electrolyte abnormalities, particularly if surgery is to be performed under general anesthesia or with the animal restrained in recumbency. Fluid therapy should be guided by analysis of serum electrolyte concentrations. An initial bolus of hypertonic (7%) saline followed by physiologic (0.9%) saline solution can be used to correct intravascular volume deficits, hyponatremia, and hypochloremia. Calcium salts can be added to the fluids if indicated. Empirical supplementation of IV fluids with potassium should be avoided because the potential for hyperkalemia always exists. Hyperkalemia can induce fatal cardiac dysrhythmias, and this effect is augmented by concurrent hyponatremia.³⁸ Administration of dextrose, sodium bicarbonate, and/or insulin (regular insulin at 0.25 to 0.4 U/kg IV slowly, SC, or IM) reduces serum potassium concentration by promoting movement of potassium from the extracellular to the intracellular space. Blood glucose should be closely monitored when insulin is administered. Uremic animals undergoing IV fluid therapy may develop pulmonary edema,³⁹ so attention must be paid to respiratory rate, auscultatory findings, and respiratory effort during fluid therapy. Slow drainage of urine from the abdominal cavity reduces pressure on the diaphragm and slows the progression of metabolic derangements caused by uroperitoneum. In long-standing cases of uroabdomen, urine may also be present in the thorax, further warranting close observation of respiratory function during anesthesia. Thoracocentesis to remove thoracic urine is indicated if respiratory function is compromised; otherwise, abdominal drainage usually induces resolution of thoracic urine accumulation.

Although bacterial infection is not considered to be a common primary cause of urolithiasis, secondary UTIs may develop after surgical intervention. Loss of the flushing effect of urination, urinary mucosal damage, impaired host cellular defenses secondary to uremia, and indwelling urinary catheter placement may contribute to the development of ascending UTI. Perioperative antibiotic therapy is therefore prudent, with due consideration of withholding times in animals intended for slaughter. Postoperative antibiotic therapy is discussed later.

SURGICAL OPTIONS

Surgical options include amputation of the obstructed urethral process, penectomy, perineal urethrostomy, prepubic urethrostomy, urethrotomy, cystotomy, tube cystostomy, and bladder marsupialization. Urethral catheterization and retrograde flushing have been used to dislodge urethral calculi and restore urine flow in a ram.⁴⁰ However, successful clearance of the urethra is rarely achieved,¹⁵ and retrograde flushing under pressure may result in urethral rupture. Retrograde passage of a catheter may allow for localization of the urethral obstruction, potentially guiding further surgical treatment. Passage of a catheter into the bladder of ruminants and camelids is difficult because of the presence of a urethral recess located near the ischial arch.⁴¹

In sheep and goats, amputation of an obstructed urethral process is a simple procedure that may at least temporarily restore urethral patency. The urethral process can be removed without detrimental effects on breeding soundness.⁴² Success rates for initial restoration of urine flow after urethral process amputation range from 37.5%³² to 66%.¹⁵ However, recurrence of urethral obstruction is extremely common, and urethral patency is often maintained for only hours to days before reobstruction occurs.^15,32 Therefore, urethral process amputation is palliative and may provide enough time to allow feeder lambs to survive until slaughter. For pet wethers, rams, and bucks, recurrence of urinary tract obstruction appears to be probable if this is the only procedure performed.

Penectomy is an option for animals intended for slaughter. Perineal urethrostomy is a surgical option for ruminants not intended to be used for breeding. In small ruminants, postoperative stricture of the stoma or recurrent obstruction with additional calculi is a long-term risk.^15,43Ischial urethrostomy with placement of a Foley catheter into the bladder has been used as a treatment for urolithiasis in heavy feedlot steers⁴⁴ and bulls.¹² If urethral damage is not severe, this procedure allows the breeding ability of bulls to be maintained.¹²

Prepubic urethrostomy has been reported in a sheep and a goat.⁴⁵ In this procedure a midperineal penectomy is performed. The perineal segment of the penis and pelvic portion of the urethra are dissected free from the surrounding soft tissue using perineal and ventral celiotomy incisions, respectively. Bilateral ileal and ischiadic osteotomies may be required to free the pelvic urethra. The urethral mucosa is then sutured to the skin of the caudoventral abdomen to create a long-lasting stoma.

Urethrotomy (removal of obstructing calculi and primary closure of urethra) is another option.^12,14 The calculi may be located, crushed with a towel clamp, and flushed from the urethral lumen, eliminating the need for a urethral incision.^12,14 Urethral stricture, adhesions resulting in phimosis in breeding males, and reobstruction with additional calculi are long-term complications.

Cystotomy allows for maintenance of breeding soundness and removal of additional calculi from the bladder. In small ruminants and camelids, bidirectional (normograde and retrograde) flushing is used to restore urethral patency.^15,32 Even if the urethra is successfully cleared of calculi, traumatic urethritis may cause significant postoperative dysuria in these animals. Therefore, some surgeons prefer also to perform a tube cystostomy to allow for rest and healing of the irritated urethra.⁴⁶ If the urethra cannot be cleared at surgery, the tube cystostomy allows for the urethra to rest, and spontaneous elimination of calculi often occurs. Alternatively, a percutaneous tube cystostomy could be performed under ultrasound guidance.

Tube cystostomy allows urine to exit the bladder through a temporary Foley or other type of suprapubic catheter, which is anchored in the bladder lumen and exits the ventral abdomen.^37,47 Urethral patency is apparently restored when calculi are spontaneously expelled from the urethra, dissolved, or refluxed into the bladder, at which time the catheter can be removed. In cases of urethral rupture where patency of the entire urethra is the preferred outcome, tube cystostomy is often the sole feasible option.⁴⁶ Primary repair of the urethral defect is rarely successful because of swelling and maceration of the damaged mucosa.

Contrast medium can be introduced into the bladder through the catheter to monitor urethral patency, locate urethral obstruction, or identify urethral rupture.²⁹ In a goat with a tube cystostomy, 30 mL of a commercially available urinary lavage product containing citric acid, glucono-delta lactone, and magnesium carbonate (hemiacidrin; Renacidin, Guardian Laboratories, Hauppauge, NY) was infused through the cystic catheter and left in the bladder for 30 minutes four times daily for 3 days.⁴⁸ This solution is acidic (pH 3.85) and was used to facilitate dissolution of calculi.

Spontaneous resolution of urethral obstruction with tube cystostomy may take several weeks or longer; a mean time of about 11 days in small ruminants has been reported.^37,47 To judge when removal of the catheter is appropriate, the cystic catheter can be clamped shut and the animal observed for urination through the urethra.

Complications of tube cystostomy have been reported to be as high as 50% with surgically placed tube cystostomies and 100% with percutaneously placed cystic catheters.⁴⁹ The primary complication is a dislodged catheter, the replacement of which necessitates a second surgery. Risk of tube dislodgement appears to be less when 18 to 20 French tubes are used, when the tube has a balloon to retain the catheter in place (Foley-type catheter), and when a purse-string suture is used in the bladder wall.^47,49 Other complications encountered include tears of the bladder, leakage of urine into the abdomen, adhesions of the bladder to intestine or body wall, and obstruction of the catheter.

In cases of bladder rupture, the urine should be drained from the abdominal cavity, and a surgical procedure should be performed to divert urine to the exterior. If primary repair of the bladder defect is desired, a laparotomy and cystotomy or tube cystostomy can be performed with the animal under local²² or general⁵⁰ anesthesia. Primary repair of the bladder defect is not always necessary, however, because spontaneous sealing of the bladder with fibrin or omentum can occur. Depending on the size and location of the bladder defect, daily or continuous abdominal drainage may need to be performed until spontaneous sealing occurs. Tears are more likely to seal spontaneously if they are located on the dorsal aspect of the bladder⁵¹; however, it is generally difficult to know the location of the bladder defect without performing a laparotomy. Abdominal drainage may be combined with perineal urethrostomy or penectomy.^12-14 Alternatively, a catheter can be secured in the bladder by a small abdominal incision⁵² or an ischial urethrotomy.^12,44

In bladder marsupialization the apex of the bladder is exteriorized using a small paramedian incision, and the seromuscular layer of the bladder is circumferentially secured to the abdominal wall. A cystotomy is performed, and the bladder mucosa is secured to the skin, creating a permanent opening for urine drainage from the bladder to the exterior.⁵³ Advantages of bladder marsupialization include decreased hospitalization time and expense for the owner. However, complications include chronic urine scalding, stricture formation, reobstruction, and bladder prolapse. Failure of bladder marsupialization was reported to be 33% in one study.⁴⁹

Ureteral calculi may be removed by ureterotomy.¹⁴Nephrectomy may be performed in unilateral cases of obstructive nephrolithiasis.⁵⁴ If unilateral nephrectomy is under consideration, measurement of BUN, serum creatinine, and urine specific gravity, with or without a biopsy of the apparently unaffected kidney, should be performed to evaluate remaining renal function.⁵⁵ Normal urine specific gravity, BUN, and serum creatinine indicate that the majority of nephrons in the remaining kidney are functional.

Multiple small stab incisions into the skin and subcutaneous tissue along the ventral abdomen may facilitate urine drainage in cases of urethral rupture. These are allowed to heal by second intention.

POSTOPERATIVE CONSIDERATIONS

Continued assessment of hydration, urine output, and serum urea nitrogen, creatinine, and electrolyte concentrations is indicated after surgery. Postobstruction diuresis has been reported in ruminants⁴⁰ and may result from tubular damage, accumulation of urea or natriuretic factors, or preoperative fluid therapy.⁵⁶ Induction of modest diuresis through fluid therapy after surgery may help to reduce azotemia and accumulation of blood clots and bacteria in the urethra.

Antimicrobial therapy with an antibiotic that achieves high urine concentrations (e.g., penicillin, ampicillin, sulfonamides) is warranted; the duration of therapy depends on the surgical procedure chosen, residue withholding considerations, and whether UTI exists at surgery. For tube cystostomy, antimicrobial therapy is recommended while the tube is in place and for at least 1 week after the tube is removed.³⁷ Antimicrobial therapy should be maintained for at least 3 weeks after surgery in animals with active UTI.

Prompt initiation of preventive dietary and environmental management is critical for the long-term success of any surgical procedure for urolithiasis (see Prevention). In animals intended for slaughter, at least 30 days is often required for resolution of tissue damage from urethral or bladder rupture.⁴⁴

Pathophysiology

MECHANISMS OF CALCULOGENESIS

Multiple factors influence the development of urinary calculi, but of primary importance is the development of high urinary concentrations of soluble, ionized minerals (crystalloids) that aggregate to form insoluble crystals. Supersaturation of urine with a calculus-forming crystalloid is a prerequisite for urolith development.⁶² However, supersaturation alone is not solely responsible for urolith initiation because normal urine is typically supersaturated with a variety of calculogenic ions.⁶³ Urine contains variable concentrations of mucopolysaccharides, ions, and organic acids, which act as intrinsic inhibitors of crystallization. Through physical and electrochemical interactions, these compounds maintain calculogenic minerals in a colloidal suspension. Calculus formation is initiated if supersaturation of urine with appropriate crystalloids exceeds the protective capabilities of the crystallization inhibitors. The crystalloids are rendered insoluble and precipitate out of the aqueous phase of urine. Calculi enlarge as further mineral precipitation takes place on the crystal surfaces. Dietary, environmental, and management influences interact to determine the degree of supersaturation of urine with calculogenic minerals. Dehydration, with resultant concentration of urinary minerals, would appear to be a potential contributing factor in the development of all types of uroliths.

Mucoproteins, which make up a variable fraction of most uroliths, may act as templates (matrices) on which calculogenic ions could initiate crystallization.⁶² Urine mucoproteins may reduce the solubility of certain crystalloids or may be passively incorporated into developing uroliths.^64,65 Estrogenic substances in the diet may promote urolithiasis by increasing urinary mucoprotein concentration.^65,66 This was of particular concern in the past, when diethylstilbestrol (DES) was used as a growth promoter in sheep and cattle in North America.⁶⁶

The solubility of some calculogenic crystalloids is influenced by urinary pH. Struvite (magnesium ammonium phosphate), calcium phosphate, and calcium carbonate uroliths are less soluble in alkaline urine, whereas calcium oxalate solubility is not affected by changes in urine pH within the physiologic range.^63,67-69 The effect of urinary pH on silica calculi is debatable,⁷⁰ but recent findings show a trend toward reduction in formation under conditions of mild aciduria.⁷¹

Primary UTI is considered an uncommon cause of ruminant urolithiasis.⁶⁸ Purulent debris within the urinary tract may serve as a nidus for crystal development, and bacterial ureases may increase urinary pH, thereby reducing the solubility of certain crystalloids. Pyelonephritis, with presumed secondary urolithiasis, has been reported in cattle.²⁶ Urolithiasis may be considered as both a rare cause²⁷ and a rare consequence²⁶ of UTI.

Although rare, vitamin A deficiency has been incriminated as a contributory factor for urolith development.⁶⁸ Metaplasia of urinary tract epithelium may create nidi for calculogenesis through desquamation of cells or altered cell surface characteristics.

Feeding patterns may influence the formation of urinary calculi. In ruminants, providing a ration in one or two feedings per day induces antidiuretic hormone (ADH) release soon after feeding, resulting in a marked but transient decline in urine output and an increase in urine concentration.^14,57 These changes in urine composition can be limited through ad libitum feeding.⁹ Water hardness (dissolved mineral content) has not been considered a significant factor in ruminant urolithiasis.⁵⁷

PHOSPHATIC UROLITHIASIS

Ruminants consuming rations high in phosphorus, such as grain-based feedlot rations, typically develop struvite calculi^9,68,72-75 or calcium phosphate (apatite) calculi.^58,76 Rations where the calcium/phosphorus ratio favors phosphorus are particularly prone to cause outbreaks of urolithiasis.^58,75 Increased dietary phosphorus levels result in increased concentration of phosphate ion in ruminant urine.⁷² Because calcium opposes phosphorus absorption from the gut, urinary excretion of phosphate is augmented by low dietary levels of calcium relative to phosphorus.^68,72,73 The interaction of magnesium with calcium and phosphorus is less clearly understood,⁷² but experimental increases in dietary magnesium levels to 0.6% of dietary dry matter induced calcium phosphate and struvite urolithiasis in calves.⁷⁴

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Pelleting of rations has been associated with an increased incidence of phosphatic urolithiasis.⁹ Ruminant saliva is rich in phosphorus, and the GI tract is the primary route of phosphorus excretion in ruminants.²⁰ In theory, ruminants feeding on pelleted rations produce less saliva, which would reduce GI phosphate losses and increase urinary phosphate excretion.⁹

SILICA UROLITHIASIS

Silica urolithiasis is primarily a problem of sheep and cattle grazing native rangeland grasses of western North America. The silica fraction of these grasses tends to increase with maturity and may continue to increase even after growth ends. In some areas, 4% to 8% of total grass dry matter may be silicon compounds.⁵⁷ A fraction of dietary silica, as unpolymerized silicic acid, is dissolved in the ruminal fluid of the grazing animal, absorbed, and excreted in the urine. In sheep and cattle on range, water intake is usually intermittent. During periods of water deprivation, avid water and sodium resorption by the kidneys results in the formation of highly concentrated urine. Silicic acid may be concentrated to such an extent that it polymerizes to a less soluble form, polysilicic acid. Polysilicic acid, in turn, forms large micelles in solution that quickly become insoluble when bound to urinary mucoproteins.⁶⁴ The resultant calculi are usually composed of about 20% mucoprotein, 75% silicon dioxide, and variable amounts of calcium oxalate and calcium carbonate.⁵⁷

Dietary deficiencies of copper and zinc have been identified as contributory factors in silica urolith formation in rats.⁷⁷ The incidence of silica urolithiasis can be increased by feeding sheep rations that have a high calcium/phosphorus ratio (∼2.8:1) and induce more alkaline urine.^71,78 It is important to note that a high calcium/phosphorus ratio in the diet can help to prevent one type of urolith (struvite) but may be a contributory factor for another (silica). This underscores the importance of both ration and urolith mineral analyses in the formulation of preventive measures for this disease.

CALCIUM CARBONATE UROLITHIASIS

Calcium carbonate calculi have a characteristic round shape and golden color and are often present as multiple calculi scattered throughout the lower urinary tract (Fig. 34-20). These calculi are common in sheep grazing lush, rapidly growing clover pastures in Australia.⁶⁹ These forages are rich in calcium and low in phosphorus and magnesium and have high oxalate content. In the gut, oxalate avidly binds calcium and makes it unavailable for absorption. With gradual introduction of oxalate-rich diets, ruminal bacteria efficiently metabolize oxalate to bicarbonate.^69,79 Thus, microbial metabolism of oxalate in the rumen may increase the availability of dietary calcium.⁸⁰ These factors may combine to increase urinary calcium excretion and alkalinize urine, thereby promoting calcium carbonate calculogenesis. Calcium carbonate urolithiasis has been reported in northern California.⁸¹ Although many of the animals in this report had a history of being fed alfalfa hay, the relationship, if any, between alfalfa feeding and calcium carbonate urolithiasis remains unclear.

Fig. 34-20 Calcium carbonate calculi.

CALCIUM OXALATE UROLITHIASIS

Oxalate is an end product of glycine and ascorbic acid metabolism and is a normal constituent of urine.^62,69 In humans, inherent defects in oxalate metabolism and calcium homeostasis contribute to calcium oxalate urolithiasis.⁶² Dietary and metabolic factors that influence formation of this urolith type have not been elucidated in ruminants. Poisoning by oxalate-containing plants is not considered a common cause of calcium oxalate urolithiasis.⁶⁸ Given its very low solubility, calcium oxalate crystals are often present in normal urine⁶⁸ and may be incorporated into other uroliths as a trace component.