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Home , Athletic incontinence, Azotemia, Hypoproteinemia

RENAL DISORDERS AND RED URINE – CONDITIONS YOU MAY NEVER HAVE CONSIDERED

Hal Schott, DVM, PhD, DACVIM Department of Large Animal Clinical Sciences D-202 Veterinary Medical Center Michigan State University, East Lansing, MI 48824-1314 (517)-353-9710 [email protected]

Acute Injury and Acute Renal Failure: Prerenal failure has long been used to describe an acute, reversible increase in nitrogenous waste products () associated with a transient decrease in renal function due to renal hypoperfusion. Although this term is entrenched in both the human and veterinary medical literature, its use likely contributes to lack of recognition of subclinical renal damage that may accompany a number of medical problems. This can be attributed to the large reserve capacity of the kidneys for which nearly 75% of function must be compromised before significant dysfunction is recognized clinically. With prerenal failure adequacy of renal function is characterized by maintenance of concentrating ability (urine specific gravity >1.035) and normal and urine concentrations. Unfortunately, urine samples are rarely collected from horses at hospital admission to document specific gravity and urine tonicity declines and urine Na+ concentration increases rapidly with supportive fluid therapy. As a consequence, it can be challenging to distinguish between prerenal failure and intrinsic renal damage (renal azotemia, for which loss of concentrating ability is a hallmark) by measuring urine specific gravity in patients that have been receiving fluids for 6-12 hours. Nevertheless, changes in glomerular and tubular function and integrity can be supported by documenting pigmenturia, , or glucosuria with reagent strip analysis or cast formation on microscopic examination of urine sediment.

Despite the reversible nature of azotemia and urinary alterations with prerenal failure, nephron injury (and a degree of nephron loss) likely occurs in most instances of prerenal failure. To increase awareness of subclinical renal damage in patients with decreased renal flow (RBF) and glomerular filtration rate (GFR), the term (AKI) has been introduced in human and, subsequently, small animal medicine. AKI is defined as an increase in serum (Cr) concentration of as little as 0.3 mg/dL (25 μmol/L) or a 50% increase from the baseline value, yet Cr may remain within the and serum electrolyte concentrations are usually normal. Further, the mild increase in Cr is reversible with appropriate supportive treatment. When AKI progresses to overt acute renal failure (ARF), abnormalities in serum electrolyte concentrations (hyponatremia, hypochloremia, and occasionally hyperkalemia), more substantial azotemia (Cr>2.5 mg/dL or 220 μmol/L), loss of concentrating ability (urine specific gravity <1.020), and clinical signs of renal failure may become apparent. In the author’s hospital the incidence of significant azotemia is a bit under 5% for horses that have a serum chemistry profile performed as part of their evaluation; however, mortality is high for patients with severe azotemia (Cr>10 mg/dL or 880 μmol/L) with the exception of neonates with spurious hypercreatininemia.

Causes: Acute kidney injury usually develops as a complication of another disease process or activity leading to and a prolonged period of decreased RBF and GFR (e.g., colic, enterocolitis, hemorrhage, or endurance exercise). AKI may progress to ARF when renal hypoperfusion persists or renal damage is exacerbated by exposure to nephrotoxic agents. Hemodynamically-mediated AKI/ARF is often associated with (urine output <0.5 mL/kg over 6 hours) while urine production with nephrotoxin-associated AKI/ARF often remains normal (nonoliguric AKI). In neonates, ARF can also develop as a complication of septicemia, particularly with disseminated Actinobacillus equilli infection. Recently, there have also been reports of ARF developing with Leptospira spp. infections in equids.

Nonsteroidal anti-inflammatory drugs: Most horses do not experience appreciable adverse effects from NSAID use as long as they are administered at the proper dose and treated animals are not dehydrated. When RBF decreases as a consequence of dehydration or diversion of cardiac output away from the kidneys (as during exercise), vasodilatory prostaglandins (PGE2 and PGI2) are produced within the kidney. Production of renal prostaglandins via cyclooxygenase (COX) pathways is greatest in medullary tissue, the region of the kidney that normally has the lowest blood flow and functions in a relatively hypoxic environment. Thus, it should not be surprising that the lesion associated with NSAID use is inner medullary (medullary crest or papillary) necrosis (Figure 1). As with adverse gastrointestinal effects of NSAIDs, it appears that certain individuals are more sensitive to the adverse renal effects of these drugs. Consequently, this author prefers use of “NSAID sensitivity” rather than “NSAID toxicity” when adverse effects are observed with NSAID treatment. Recent development of more COX-2 selective NSAIDs has received considerable attention and it would logical to assume that use of these NSAIDs may be less nephrotoxic than use of other non-specific NSAIDs. However, this new generation of COX-2 selective NSAIDs has not been demonstrated to be renoprotective in studies in other species and should not be assumed to be renoprotective in equids.

Figure 1. Medullary necrosis associated with NSAID use. Renal function in both of these patients had returned to normal yet gross renal lesions were apparent as green-to-brown discoloration (left, yellow arrows) or actual cavitary lesions with tissue loss (right, blue arrows) after euthanasia was performed for refractory laminitis.

Aminoglycoside antibiotics: Aminoglycoside antibiotics accumulate within proximal tubular epithelial cells with repeated administration of the drugs. Once toxic amounts are sequestered within the tubular cell, cellular is disrupted, and cell swelling, death, and sloughing into the tubular lumen occur. Most cases of aminoglycoside nephrotoxicity are not the result of overdosing or administration of the drug to an azotemic patient. In fact, healthy kidneys can usually tolerate a single major overdose (10 times the normal dose) without detrimental effects. Similarly, delaying administration of the initial dose of an aminoglycoside antibiotic until dehydration is corrected is unlikely to be renoprotective and may compromise treatment of sepsis. If initial laboratory data reveals moderate azotemia (e.g., Cr>5 mg/dL or 440 μmol/L) consideration of an alternative to aminoglycoside antibiotics for antimicrobial therapy is warranted, but a single previously administered therapeutic dose of an aminoglycoside is unlikely to significantly exacerbate AKI. When aminoglycoside antibiotics must be administered to high-risk patients (those with persistent subclinical dehydration or sick neonates) for treatment of specific bacterial infections, volume deficits must be minimized and Cr should be monitored closely. In practice, nephrotoxicity more commonly develops with repeated administration of the drugs for a week or longer during treatment of pleuropulmonary or musculoskeletal infections. Affected horses often appear adequately hydrated and maintain a reasonable appetite. Thus, development of moderate azotemia, indicative of ARF, can be a surprise when serum chemistry analysis is performed as part of patient monitoring. This finding would warrant consideration of alternative antimicrobial drugs as well as discontinuation of NSAIDs. Because tubular absorption and accumulation of aminoglycosides is directly related to serum aminoglycoside concentration, the current standard practice of once daily administration has reduced the risk of nephrotoxicity as compared to multiple daily doses that were administered in the past. Because aminoglycoside antibiotics have a concentration-dependent action against bacteria, once daily dosing both ensures a higher peak serum concentration for antibacterial action while also allowing for a longer period at which the drug concentration is below the trough value. Since renal tubular damage is usually sustained only when the drug is above the trough concentration, once-daily dosing can be considered “renoprotective”. Finally, in high-risk patients repeated urinalysis may be warranted at 2-3 day intervals to detect early tubular damage by finding changes in urine protein excretion or increased gamma-glutamyl transferase (GGT) activity. apical membranes have a highly developed brush border rich in GGT and activity of this enzyme, often expressed as a ratio to urine Cr (normal value for GGT/Cr is <25 IU/g) increases in urine as tubular epithelial cells are sloughed into the lumen. This urine biochemical abnormality may be detected several days before onset of azotemia; however, many clinicians consider this test “too sensitive” to support discontinuation of aminoglycoside therapy when indicated for specific treatment of an infection. An alternative to discontinuing use of these drugs may be to further extend the dosing interval to 36-48 hours after the initial 7-10 days of once daily administration.

Clinical signs: Clinical signs in horses with AKI commonly reflect the primary disease process: colic, diarrhea, restricted gait and pigmenturia due to rhabdomyolysis, or post-exercise exhaustion. Subtle clinical signs that should prompt investigation of progression to ARF include greater lethargy or inappetance than are typically manifested with the primary disease, especially in patients with nonoliguric ARF. Persistent or oliguria followed by development of in the face of supportive fluid therapy, along with weight gain due to fluid retention, are more obvious clinical signs of ARF. Pigmenturia may be seen with rhabdomyolysis or hemolytic syndromes and gross hematuria may also be observed with more severe NSAID damage, although lithiasis and lower urinary tract disorders should first be excluded as the cause of hematuria. Occasionally, horses with severe ARF may develop marked conjunctival edema and they may also become ataxic or manifest cerebral dysfunction, a metabolic encephalopathy with similarities to hepatic encephalopathy. Diarrhea and laminitis may ensue in more serious cases. Unfortunately, development of more serious problems is usually associated with a poor outcome.

Diagnosis: As described above, AKI should be considered a silent concurrent disorder with many medical and surgical problems and progression to ARF should be suspected in patients showing more severe lethargy and anorexia than would be expected with the primary disease process. Failure to produce urine within 6-12 hours of initiating fluid therapy should be a “red flag” for oliguric ARF but may be overlooked while attention is focused on performing diagnostic procedures and providing intensive supportive care. Rectal palpation in horses with ARF may reveal mildly enlarged, painful kidneys in some patients and enlargement can be confirmed by renal ultrasonography (>20 cm length in a 500 kg horse). Renal ultrasonography may also reveal a hypoechoic rim of perirenal edema, increased echogenicity of the renal cortex (making distinction between the cortex and medulla more apparent), and/or dilation of renal pelvis. In addition to documenting presence of both kidneys, renal ultrasonography can also identify previously unrecognized evidence of chronic (e.g., unilateral hypoplasia or nephrolithiasis). At necropsy, the renal cortex with ARF is typically pale and bulges on cut section due to edema.

A diagnosis of ARF is confirmed on the basis of history, potential exposure to nephrotoxins, clinical signs, and laboratory findings. With regard to the latter, the increase in Cr is often several-fold greater (2.5-15 mg/dL or 220-1320 μmol/L) than that for blood nitrogen concentration (BUN, to 30-100 mg/dL, 10-36 mmol/L). Hyponatremia, hypochloremia, and hypocalcemia are usually present and, in more severe cases, hyperkalemia, hyperphosphatemia, and metabolic acidosis may also be detected. With oliguria or uroabdomen hyperkalemia can be severe (>7 mmol/L) and may precipitate life-threatening cardiac arrhythmias (sine wave configuration and ventricular fibrillation).

Urinalysis should be performed on all horses in which ARF is suspected. Low urine specific gravity (<1.020) and increases in urine Na+ concentration (>20 mEq/L) and fractional Na+ clearance (>1%) in the face of dehydration and gross or microscopic hematuria and proteinuria are common findings. In the absence of , detection of glucosuria and increased urinary GGT activity would support proximal tubular damage. Examination of urine sediment may reveal casts and increased numbers of erythrocytes and leukocytes while the amount of urine crystals may be decreased. Again, specific gravity and urine Na+ concentration are best assessed in urine samples collected prior to initiation of fluid therapy. Dietary salt supplementation can also increase urine Na+ concentration and confuse interpretation of results.

Treatment: Initial treatment of AKI/ARF should focus on judicious fluid therapy to replace volume deficits and correct electrolyte and acid-base abnormalities. These are more often a consequence of the primary disease rather than associated AKI/ARF. Na+, K+, and Cl- replacement may be required in horses with non-oliguric to polyuric ARF and can be accomplished by IV administration of a polyionic replacement fluid or through electrolyte supplementation in concentrate feedings or as oral slurries. Over the past few years overzealous fluid therapy has been recognized to increase morbidity and mortality from ARF in human intensive care units and efforts are being made to moderate this practice by limiting fluid support to maintenance needs alone. Serum K+ concentration in horses with nonoliguric ARF is usually normal or it may be low if they have been inappetant for several days and have depletion of body K+ stores. In contrast, with anuria or post-renal azotemia (obstruction or rupture leading to uroabdomen), specific therapy intended to lower serum K+ may be necessary. Treatment of hyperkalemia initially includes volume expansion by administration of K+-free IV fluids (0.9% NaCl solution). Oral administration of a carbohydrate (molasses or Karo syrup) or addition of dextrose to IV fluids (2-5% solution depending on administration rate, targeting a goal of 50 g/h for a 500 kg horse) is also indicated to stimulate insulin release in order to increase activity of the Na+/K+ATPase pumps to drive K+ intracellularly. With alterations in the electrocardiogram consequent to hyperkalemia (usually progressing through peaked T waves, widening of the QRS complex, loss of P waves, sine wave configuration, and ultimately to ventricular fibrillation and asystole), intravenous administration of a calcium gluconate solution may be helpful in counteracting the effects of hyperkalemia on excitable membranes. Slow administration (over 3- 5 minutes) of 100 mL of a 23% calcium gluconate solution is relatively safe and would provide 2.1 g of calcium or about 25% of the calcium in the extracellular fluid space of a 500 kg horse. As an alternative, 250 mL of a 23% calcium gluconate solution can be added to a 5 L bag of 0.9% NaCl and administered over 30-60 minutes. With uroabdomen perhaps the most important treatment to correct hyperkalemia is concurrent drainage of the K+-rich fluid (urine) from the abdomen.

In horses with prerenal failure (AKI), rather than intrinsic ARF, Cr should decrease by at least 30-50% within the initial 24 hours of supportive therapy. In contrast, Cr often remains unchanged, or may increase, with ARF. In horses that remain oliguric after 12-24 hours of appropriate fluid and electrolyte replacement, furosemide (1-3 mg/kg, IV, q 2 h) can be administered. Unfortunately, furosemide treatment is often ineffective in increasing urine output in horses with ARF because diminished tubular secretion of the drug prevents it from reaching the Na+/K+/2Cl- cotransporter on the apical membrane of epithelial cells in the ascending limb of Henle’s loop. If urine is not voided after the second dose, administration of mannitol (0.5-1 mg/kg, IV, as a 10-20% solution) can be instituted, although use of this osmotic diuretic is controversial in human intensive care units. Renal arterioles contain dopamine type 1 receptors and a constant rate infusion of dopamine (3 µg/kg/min) increases RBF, GFR, and urine output by normal kidneys of several species including horses. Consequently, this drug has been used for several decades for treatment of anuric ARF in human intensive care units and is recommended in older equine texts. However, metaanalysis of dopamine use in human patients with ARF have revealed that this treatment has had limited impact on improving survival while it also posed a risk of inducing or exacerbating cardiac arrhythmias. Thus, dopamine is no longer a recommended treatment and has been replaced by dopamine type 1 receptor agonists (e.g., fenoldopam) with more specific effects on renal arterioles and less adverse effects. In horses, oliguria should progress to within 48-72 hours after development of ARF for the prognosis for recovery to remain reasonable. Fortunately, the majority of horses with ARF are nonoliguric rather than oliguric and administration of furosemide or mannitol is unnecessary. When oliguria persists for more than 72 h, the prognosis becomes grave and peritoneal may be attempted, but success of this treatment has not been well documented in horses and should realistically only be pursued as an alternative to euthanasia.

After volume deficits have been corrected and polyuria has been achieved, patients usually only require fluid therapy until they return to eating and drinking. There is little benefit of further fluid therapy to promote a more rapid decrease in Cr. In some instances Cr may not decrease below the upper limit of the reference range for several weeks or may remain elevated if the horse has sustained substantial permanent nephron loss leading to . As long as the horse is eating and drinking well, it is reasonable to discharge the patient from the hospital for further recovery. Access to pasture that is high in water and rich in omega-3-fatty acids is an ideal diet for recovery from ARF.

Prognosis: The prognosis for recovery from AKI has generally been considered favorable as long as appropriate supportive care is provided and the horse is successfully treated for the underlying primary disease. In contrast, the prognosis for recovery from ARF remains guarded and mortality in patients in human intensive care units is nearly twice as high in those that also develop AKI. Further, more recent long-term follow-up studies of human patients with AKI that were successfully treated also reveal a nearly 10-fold increase in risk for future development of chronic kidney disease.

Chronic kidney disease: A similar change in terminology has been adopted in human and small animal medicine for patients with chronic renal disease. Rather than describing patients as have chronic renal failure (CRF, often an end stage problem), the term chronic kidney disease (CKD) has been introduced to shift attention to detection of earlier stages of chronic renal disease. Although CKD is by nature a progressive disorder, early detection and interventions may slow the rate of progression thereby prolonging life and, for people, delaying the potential need for renal replacement therapy.

CKD in the horse may be divided by clinical and pathologic findings into two broad categories: glomerular disease () and tubulointerstitial disease (chronic interstitial nephritis). However, pathology in one portion of the nephron usually leads to altered function and eventual pathology in the entire nephron such that CKD is an irreversible disease process characterized by a progressive decline in GFR. However, the rate of decline in GFR is variable making the short-term (months to a couple of years) prognosis guarded to favorable while the long-term prognosis remains poor. Unfortunately, because renal disease is often advanced when horses are first presented for clinical evaluation, the inciting cause leading to CKD may be difficult to ascertain, and end stage kidney disease (ESKD) may be the pathologic diagnosis.

Clinical signs and laboratory findings: The most common clinical sign observed in horses with CKD is weight loss (Figure 2). A small plaque of ventral edema, between the forelimbs, is another frequent finding. Moderate polyuria and polydipsia (PU/PD) are also usually present. Often, urine produced by horses with CKD is light yellow in color and transparent as it is relatively devoid of normal crystals and mucus. Accumulation of dental tartar, especially on the incisors and canine teeth, gingivitis, and oral ulcers are other findings that may be detected in horses with CKD. Decreased performance may be an early complaint in competitive horses while growth may be stunted in young horses with renal hypoplasia or dysplasia.

Laboratory findings in horses with CRF vary depending on diet and the cause and extent of renal damage. Most horses with clinical signs of CRF have moderate to severe azotemia (Cr usually 5 mg/dl or greater). The BUN to Cr ratio may vary, depending on protein intake, muscle mass, hydration and degree of azotemia but is usually >10. Mild hyponatremia and hypochloremia may

Figure 2. The most common presenting complaint for horses with chronic renal failure is weight loss (left) and, in some horses, excessive dental tartar (right) is found on the canine teeth. accompany CKD but serum concentrations of these can often remain within reference ranges. Hypercalcemia, with serum concentrations sometimes approaching 20 mg/dl, appears to be a laboratory finding that is unique to horses with CKD. Hypercalcemia is not a consequence of hyperparathyroidism as parathormone concentrations are not elevated in horses with this finding. The magnitude of hypercalcemia is dependent on diet and high values can return to the reference range within a few days of changing from alfalfa to grass hay. Acid-base balance usually remains normal until CKD becomes advanced but metabolic acidosis may be found in horses with end stage disease. Many horses with CKD are moderately anemic (packed cell volume 25-30%) likely due to decreased erythropoietin production. Horses with glomerulonephritis may have and while horses with advanced CKD of any cause may also have mild hypoproteinemia due to intestinal ulceration.

Urinalysis findings may vary depending on the cause of CKD. As mentioned, urine is relatively devoid of normal mucus and crystals making samples transparent. Further, a hallmark of CKD is urine specific gravity in the isosthenuric range (1.008 to 1.014), although heavy proteinuria in an occasional horse with glomerulonephritis may produce values up to 1.020. Quantification of urine protein concentration is required to accurately assess proteinuria. Urine protein concentration in normal horses is usually less than 100 mg/dl and the urine protein to Cr ratio should be less than 0.5:1. With significant proteinuria, urine protein to Cr ratio is usually greater than 1:1. Horses with chronic interstitial nephritis usually do not have significant proteinuria.

Diagnosis: A diagnosis of CKD is most commonly made in horses with azotemia and isosthenuria that present with a complaint of weight loss and/or decreased performance. Detection of hypercalcemia also strongly supports CKD. Rectal examination may be helpful. Horses with ureteral calculi, often have enlarged that can be palpated as they course through the retroperitoneal space (Figure 3). Although kidneys of horses with CKD are typically small with an irregular surface, these changes are not always apparent on palpation of the left kidney. Ultrasonographic imaging is useful for evaluating kidney size and echogenicity and may reveal fluid distention (, pyelonephritis, or polycystic disease) and/or presence of nephroliths (Figures 4&5). Horses with significant renal parenchymal damage and fibrosis often have increased echogenicity of renal tissue that may be similar or even greater than that of the spleen.

Figure 3. Kidneys from a horse with chronic renal failure: both kidneys are small, firm, and irregular on the surface and the proximal portion of the right is enlarged with a firm structure (ureterolith, arrow) in the lumen. Both of these abnormalities could be detected by rectal palpation.

Figure 4. Ultrasonographic image (left) and gross pathology of a kidney from a 9-year-old Shetland pony mare with chronic renal failure consequent to glomerulonephritis

Treatment: Treatment of horses with CKD is most likely to produce improved renal function if there is an acute, reversible component exacerbating CKD (acute on chronic syndrome). If an acute component is detected, it should be corrected rapidly (as described for AKI/ARF) with the goal of minimizing further loss of functional . Further, surgical removal or fragmentation of stones via lithotripsy may be indicated in horses with calculi that are thought to be causing obstruction of urine flow. Treatment of horses with stable CKD consists of supportive care: providing sufficient water, electrolytes, and nutritional support. In addition to Cr, serum electrolyte concentrations and acid-base balance should be measured regularly. Although no adverse effects of hypercalcemia in horses with CKD have been documented, decreasing calcium intake (replacing alfalfa or other legume hays with grass hay) may result in a return of serum calcium concentration to the normal range. NSAIDs are best avoided in horses with CKD.

Nutritional management aimed at maintaining body condition is the most important aspect of supportive care of horses with CKD. Access to good quality pasture, increasing carbohydrate

Figure 5. Ultrasonographic images of the left kidney of two horses afflicted with chronic renal failure: left kidney (a) of a yearling with chronic interstitial nephritis that developed 11 months following treatment with an aminoglycoside antibiotic and flunixin meglumine for a leg wound, note the generalized increase in echogenicity of the renal parenchyma in comparison to the spleen; left kidney (b) of the same yearling with the probe aimed in a different plane revealing a large nephrolith adjacent to the renal pelvis; left kidney (c) of a stallion with an obstructive ureterolith causing hydronephrosis, note the small nephrolith in the center of the image producing an acoustic shadow; left kidney (d) of the same stallion imaged in a plane rotated 90o revealing hydronephrosis consequent to obstructive disease; left kidney (e) of the same stallion following relief of ureteral obstruction by electrolhydraulic lithotripsy, note that the kidney is small and renal parenchyma has a diffuse increase in echogenicity due to renal fibrosis.

(grain) intake, and adding fat to the diet are recommendations to increase caloric intake. Over the past couple of decades restricting dietary protein intake by human and veterinary patients with CKD was thought to have beneficial effects; 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. Adequacy of dietary protein intake can be assessed by the BUN to Cr ratio: values >15 suggest excessive protein intake while values <10 may indicate protein-calorie malnutrition.

Progressive loss of nephron function with CKD precludes successful long-term treatment. However, horses with early CKD may be able to continue in performance or live as pets for quite some time (months to a few years). In general, as long as Cr remains <5 mg/dL and the BUN:Cr ratio is <15, horses seem to maintain a fair attitude, appetite, and body condition. However, once Cr exceeds 5 mg/dL, the rate of progression of CKD appears to accelerate and signs of (anorexia, poor hair coat, and loss of body condition) become more apparent. Due to the variable nature of progression, each case should be handled on an individual basis with the emphasis on maintenance of body condition until humane euthanasia becomes necessary.

Hematuria: Hematuria can be presenting complaint for a variety of disorders of the urinary tract. The problems causing hematuria can range from relatively minor disorders to more severe disease processes that may result in life-threatening hemorrhage. Urolithiasis and neoplasia are common causes of hematuria. Other causes of hematuria include exercise-associated hematuria, proximal urethral tears in stock type horses, idiopathic renal hematuria, and idiopathic cystitis.

Normal urine contains about 5,000 RBC/mL or <5 RBC/hpf on sediment examination. Microscopic hematuria (10,000-2,500,000 RBC/mL) can be detected as an increase in RBCs on sediment examination (10-20/hpf) or a trace to +++ reaction on reagent strip testing of urine. It is important to recognize that reagent strip results, that utilize the peroxidase-like activity of hemoglobin and to oxidize a chromogen in the test pad, do not differentiate between hemoglobin and myoglobin. Thus, positive results are not specific for hematuria and may be more appropriately termed pigmenturia. Despite this limitation, reagent strips can be used to differentiate hematuria from hemoglobinuria or myoglobinuria when the color change is limited to scattered spots on the test pad. This pattern implies that intact RBCs were adsorbed onto the pad, underwent lysis, and produced a localized color change due to hemoglobin activity on the chromogenic substrates. Macroscopic or gross hematuria can be observed with >2,500,000- 5,000,000 RBC/mL (about 0.5 mL of blood per liter of urine). Macroscopic hematuria can be differentiated from other causes of pigmenturia by centrifuging a sample of urine to produce a red cell pellet and clear supernatant urine.

Noting the timing of hematuria can be useful to localize the site of urinary tract hemorrhage. Hematuria throughout urination is consistent with hemorrhage from the kidneys, ureters, or bladder, whereas hematuria at the beginning of urination is often associated with lesions in the distal . Hematuria at the end of urination is usually the result of hemorrhage from the proximal urethra or bladder neck. A thorough diagnostic evaluation, including physical examination, rectal palpation, analyses of blood and urine, endoscopy of the lower tract, and ultrasonography, is usually rewarding in establishing the source and cause of urinary tract hemorrhage.

Urolithiasis: The presence of uroliths at any level of the urinary tract may cause mucosal irritation and hemorrhage, resulting in hematuria. The classic presenting complaint for a cystolith in a gelding is post-exercise hematuria while horses with urethroliths may have incontinence or urinary obstruction and signs of colic, often with a dropped penis. Stones in both locations may also cause painful urination, including stranguria and pollakiuria. Rectal examination is usually rewarding in confirming presence of cystoliths while urethroliths are commonly lodged at or just below the pelvic brim. The latter can be palpated externally and the urethra above the obstructing urethrolith is often quite distended. When palpating for a suspected cystolith, it is important to remember that and pollakiuria frequently result in a small bladder that may be entirely within the pelvic canal. In this situation, the bladder and disc-shaped cystolith are best palpated with the hand inserted only wrist deep into the rectum. If the hand is inserted further forward to search for the bladder in the expected location over the brim of the pelvis, a cystolith can be missed as it may be lying just under the wrist or forearm. In contrast, the bladder may be markedly enlarged with an obstructive urethrolith.

Equine uroliths are composed of calcium carbonate crystals, with varying amounts of phosphate, and are not amenable to dietary dissolution. Thus, treatment of cystoliths consists of surgical removal and a variety of procedures exist. During preparation for surgery, the author recommends collection of a catheterized urine sample for quantitative bacterial culture as concurrent urinary tract infection may accompany urolithiasis. In addition, either the entire stone or a portion of the cystoliths should also be submitted for culture after removal as recovery of bacteria is higher from stones than urine samples. Nephroliths and ureteroliths carry a more guarded prognosis, especially with bilateral disease resulting in chronic kidney disease, although removal via ureterotomy or nephrectomy can be an effective treatment in patients with obstructive unilateral disease.

Urinary Tract Neoplasia: Hematuria is the most common presenting complaint for neoplasia of the kidneys, ureters, bladder, and/or urethra. Adenocarcinoma is the most common renal tumor and sqaumous cell carcinoma is the most common neoplasm of the bladder and urethra. Physical, rectal, laboratory, cystoscopic, and ultrasonographic examinations are usually rewarding in locating the neoplasm. Treatment is usually unsuccessful unless a focal neoplasm can be removed by nephrectomy or partial resection of the bladder. Neoplasms affecting the distal urethra (squamous cell carcinoma or sarcoid) may also be amenable to surgical resection and local antineoplastic therapy with 5-fluoruracil or cisplatin.

Exercise-associated hematuria: Exercise is accompanied by increased filtration of RBCs across the glomerular barrier. Typically, hematuria is microscopic but occasionally gross discoloration of urine may be observed. Gross hematuria is likely a consequence of bladder mucosal erosions that are traumatically induced by abdominal contents pounding the bladder against the pelvis during exercise (Figure 6). A history of emptying the bladder immediately prior to a high intensity exercise bout would increase the risk of developing this problem as would prolonged low intensity exercise (often referred to as the “bongo drum bladder” in endurance horses). Although apparently non-painful to the horse, owners of affected equine athletes are often quite concerned about gross hematuria after exercise. Detection of focal bladder erosions or ulcers with a contrecoup distribution during cystoscopy with 48 hours after onset of hematuria may confirm this problem; however, a diagnosis of exercise-associated hematuria is often one of exclusion after diagnostic evaluation has ruled out other causes of hematuria such as a cystolith. Exercise-associated hematuria is a self-limiting problem as the bladder mucosal lesions heal within a few days.

Figure 6. Bladder mucosal erosions in a Standardbred mare with gross hematuria following exercise attributed to “bruising” of the mucosa in a “contrecoup” fashion due to trauma of the bladder against the pelvic brim during exercise. Urethral tears: Although a recognized cause of hemospermia in stallions, tears of the proximal urethra at the level of the ischial arch are also one of the more common causes of hematuria in geldings. Because the tears often heal into fistulas by the time diagnostic evaluation is pursued, they can be difficult to detect without use of high-resolution videoendoscopic equipment and prior knowledge of the common appearance and location of the lesion(s). Consequently, hematuria has also been attributed to UTI, urethritis, or hemorrhage from "varicosities" of the urethral vasculature. Urethral tears typically result in hematuria at the end of urination, in association with urethral contractions. Affected horses generally void a normal volume of urine that is not discolored. At the end of urination, affected geldings have a series of urethral contractions resulting in squirts and dripping of bright red blood from the end of the penis. In most instances, the condition does not appear painful or result in pollakiuria. Treatment with antibiotics for a suspected cystitis or urethritis has routinely been unsuccessful, although hematuria resolves spontaneously in some cases.

Examination of affected horses is often unremarkable. In contrast, horses with hematuria due to urolithiasis or neoplasms involving the penis are usually presented with additional complaints such as pollakiuria, a foul odor to the sheath, or presence of a mass on the penis. With urethral tears, laboratory analysis of blood reveals normal renal function although mild anemia (packed cell volume 25-30%) can be an occasional finding. Urine samples collected by mid-stream catch or bladder catheterization appear grossly normal. Urinalysis may have normal results or there may be an increased number of RBCs on sediment examination, a finding that would also result in a positive reagent strip result for blood. Bacterial culture of urine yields negative results. As mentioned, the diagnosis is made via endoscopic examination of the urethra during which one or more lesions are typically seen along the dorsocaudal aspect of the urethra at the level of the ischial arch (Figure 7). With hematuria of a few weeks duration, the lesion may appear as a depressed fistula communicating with the vasculature of the corpus spongiosum penis (CSP, cavernous vascular tissue surrounding the urethra). 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 via the endoscope as movement within the urethra.

Figure 7. Proximal urethral tears at the level of the ischial arch in two geldings: lesions are outlined by the yellow arrows (left and right images) while the middle image shows haemorrhage into the urethral lumen immediately following urination.

Urethral tears likely develop as a "blowout" of the CSP into the urethral lumen. Contraction of the bulbospongiosus muscle during ejaculation causes increased pressure in the CSP, 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 proposed explanation for the hematuria at the end of urination in horses with urethral tears is a sudden decrease in intralumenal urethral pressure while pressure within the CSP remains high. Once the lesion has been created, it is maintained by recurrent at the end of urination and the surrounding mucosa heals by formation of a fistula into the overlying vascular tissue. Interestingly, the majority of affected geldings are stock type horses (Quarter horses and Paints) and, although undocumented, an anatomical predisposition in these breeds could be speculated. Close inspection of the perineum in affected geldings may reveal either asymmetry or a widened perineal space under the tail.

Since hematuria may resolve spontaneously in some geldings, no treatment may be initially required. If hematuria persists for more than a month or if significant anemia develops, a temporary subischial perineal urethrotomy (PU) is performed. With sedation and epidural or local anesthesia, a vertical incision is made over a catheter which has been placed in the urethra. The incision is extended through the fibrous sheath surrounding the CSP but not into the urethral lumen to form a “pressure relief valve” or path of lower resistance for blood to exit the CSP at the end of urination. The surgical wound requires a couple of weeks to heal and moderate hemorrhage from the PU site onto the hind limbs is apparent for the first few days after surgery. Additional treatment consists of local wound care and prophylactic antibiotic treatment (typically a trimethoprim/sulfonamide combination) for 4-7 days. Hematuria should resolve within a week following this procedure.

Idiopathic renal hematuria: Idiopathic renal hematuria (IRH) is syndrome characterized by sudden onset of gross hematuria. 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 (Figure 7). Although a definitive cause of renal hemorrhage may be established in some horses (renal adenocarcinoma, arteriovenous or arterioureteral fistula, etc.), the disorder is termed idiopathic when a primary disease process cannot be found. Both sexes and a wide age range have been affected; however, the majority of equids with IRH have been Arabian or part-Arabian horses.

Figure 7. Urination in horses with idiopathic renal hematuria is accompanied by passage of blood clots (left) and cystoscopic examination usually reveals blood clots passed with urine from one of the ureteral orifices (right).

Use of the term idiopathic renal hematuria to describe this syndrome in horses was adapted from its use in human patients and dogs with severe renal hemorrhage. In humans and dogs, hematuria is more commonly a unilateral than a bilateral problem, similar to what has been observed in affected horses. Horses affected with IRH appear to have spontaneous, severe hematuria in the absence of other signs of disease. In affected Arabian horses managed by the author, neither UTI nor urolithiasis has been detected and the magnitude of hematuria has resulted in need for repeated blood transfusions. As with hemorrhage associated with guttural pouch mycosis, the syndrome may produce episodic hemorrhage with spontaneous resolution. The magnitude of hematuria is considerably greater with IRH than with urolithiasis or urinary tract infection, pyuria is absent, and urine culture results are negative. In the author’s experience, one or two initial episodes of hemorrhage are followed by a more severe hemorrhagic crisis within months to a couple of years following observation of the initial bleeding episode. Of interest, has been notably absent in the history of affected horses.

A diagnosis of IRH is made by exclusion of systemic disease, other causes of hematuria, and alterations in hemostasis. Physical examination may reveal , tachypnea, and pale membranes consistent with acute blood loss. An enlarged, irregular bladder may be found on rectal palpation due to presence of blood clots. Azotemia, if present, is generally prerenal and resolves with fluid therapy. Endoscopic examination is important to document that hematuria is originating from the upper urinary tract and to determine whether hemorrhage is unilateral or bilateral. 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.

Treatment for IRH consists of supportive care for acute blood loss, including blood transfusions. Medications intended to promote hemostasis (-amino-caproic acid, formalin, etc.) have also been administered but their efficacy has not been validated. Since the condition may be self- limiting in some patients, supportive care is warranted. With severe and recurrent hematuria of unilateral renal origin, a nephrectomy may be indicated. A nephrectomy is best pursued when an underlying cause for hematuria (e.g., nephrolith, renal neoplasia, or vascular anomaly) can be found and when function of the affected kidney is markedly decreased. In the author’s experience, nephrectomy of the affected kidney in two Arabian mares was followed by development of hematuria from the contralateral kidney within 10 days of nephrectomy. Thus, nephrectomy in Arabian or part-Arabian horses with IRH is no longer recommended. To date, the author has managed eight Arabian horses with IRH and all required euthanasia within 2 years of initial diagnosis.

Idiopathic cystitis-painful bladder syndrome: Idiopathic or interstitial cystitis is an important cause of pelvic and bladder pain in humans, predominantly women. Although the syndrome remains somewhat poorly defined, pelvic (bladder) pain and with urgency have a serious detrimental impact on affected patients’ quality of life. Unlike typical cystitis, urine cultures yield negative results and treatment with antibiotics provides little relief. Approximately 25% of affected humans also have microscopic hematuria. A similar syndrome of idiopathic cystitis-painful bladder has also been described in cats.

The author has seen two horses with a somewhat similar clinical syndrome of idiopathic cystitis. Of interest, both were geldings and they presented for evaluation of macroscopic hematuria in combination with pollakiuria and mild intermittent colic signs. Both had negative urine cultures but the bladder wall was subjectively thickened on rectal palpation. Cystoscopic examination revealed fairly diffuse submucosal and mucosal hemorrhage within the bladder (Figure 8).

Figure 8. 8-year-old pony gelding was presented for intermittent, mild colic signs and haematuria of 3 days duration. Haematuria (left) and pollakiuria were observed in the holding stall. Cystoscopic examination revealed diffuse submucosal haemorrhages in the bladder wall. Treatment with a 5-day course of a trimethoprim- sulfonamide combination and phenylbutazone resulted in marked improvement in clinical signs within 2-3 days and repeat cystoscopy 3 weeks later revealed more than 90% improvement of bladder lesions.

The cause of interstitial cystitis remains poorly defined although thickening of the bladder wall and mast cell infiltration are present in many cases. Increased uroepithelial permeability is a feature of the syndrome in humans that allows leakage of substances high in urine (notably potassium) into the deeper layers of the bladder wall, causing stimulation of pain receptors and clinical signs. Management of idiopathic cystitis in humans and cats involves lifestyle and dietary changes. Specifically, stress management is combined with avoidance of certain foods that lead to increased urinary excretion of irritating substances. In addition, analgesic and psychoactive drugs are used.

In both geldings seen by the author, fairly dramatic clinical improvement was reported by their owners within a few days of starting treatment with antimicrobial and analgesic medications (phenylbutazone). Because no bacteria were cultured from urine samples, it is suspected that the analgesic medication was the most effective treatment. Finally, because these two geldings had fairly dramatic clinical signs, it raises a question as to whether or not this disorder may be more common, yet largely unrecognized, in horses.

References

Acute kidney injury and failure Geor RJ. Acute renal failure in horses. Vet Clin North Am: Equine Pract 2007;23:577. Bartol JM, Divers TJ, Perkins GA. Case presentation: Nephrotoxicant-induced acute renal failure in five horses. Compend Cont Educ Pract Vet 2000;22:870.

Chronic kidney disease Schott HC. Chronic renal failure in horses. Vet Clin North Am: Equine Pract 2007;23:593. Ehnen SJ, Divers TJ, Gillette D, et al. Obstructive nephrolithiasis and ureterolithiasis associated with chronic renal failure in horses. J Am Vet Med Assoc 1990;197:249. Van Biervliet J, Divers TJ, Porter B, et al. Glomerulonephritis in horses. Compend Contin Educ Pract Vet 2002;24:892.

Hematuria Schumacher J, Schumacher J, Schmitz D. Macroscopic hematuria of horses. Equine Vet Edu 2002;14:201. Schumacher J. Hematuria and pigmenturia of horses. Vet Clin North Am: Equine Pract 2007;23:655. Schott HC, Hodgson DR, Bayly WM. Hematuria, pigmenturia and proteinuria in exercising horses. Equine Vet J 1995;27:67. Schumacher J, Varner DD, Schmitz DG, et al. Urethral defects in geldings with hematuria and stallions with hemospermia. Vet Surg 1995;24:250. Taintor J, Schumacher J, Schumacher J, et al. Comparison of pressure within the corpus spongiosum penis during urination between geldings and stallions. Equine Vet J 2004;36:362. Schott HC, Hines MT. Severe urinary tract hemorrhage in two horses (Letter). J Am Vet Med Assoc 1994;204:1320. Vits L, Araya O, Bustamante H, et al. Idiopathic renal Hematuria in a 15-year-old Arabian mare. Vet Rec 2008;162:251.