Red urine: Disorders you may have never considered (Proceedings)

Hematuria

Hematuria can be a 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, urinary tract infection, drug toxicity, and neoplasia are some of the more common causes of hematuria. For this presentation, three less commonly recognized causes of hematuria are described: i) exercise-associated hematuria, ii) proximal urethral tears in stock type horses, and iii) idiopathic renal hematuria. Before these specific conditions are discussed, a brief overview of hematuria is warranted.

Normal urine contains about 5000 (range 2000 to 10,000) red blood cells (RBCs) per ml. This range of RBC excretion should yield negative results on reagent strip analysis and a report of not more than 5 RBCs per high-power field (hpf) on sediment examination. Increases in RBC excretion may lead to microscopic or macroscopic hematuria. Microscopic hematuria, which implies an increase in RBC excretion that cannot be seen grossly, is usually associated with increases in the range of 10,000 to 2,500,000 RBC per ml. On sediment examination at least 10 RBC/hpf should be apparent. Reagent strip analysis results can range from trace to +++. It is important to recognize that reagent strip results, that utilize the peroxidase-like activity of hemoglobin and myoglobin 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. Ability to differentiate hematuria from excretion of the heme pigments is limited to a threshold of 250,000 to 300,000 RBCs per ml, unless urine samples are diluted with normal saline.

Macroscopic or gross hematuria indicates RBC excretion in excess of 2,500,000 to 5,000,000 RBC per milliliter (or about 0.5 mL 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 yellow supernatant urine. In concentrated urine (specific gravity over 1.020), RBCs tend to become crenated, owing to osmotic shift of water out of the cells. In urine with a specific gravity below 1.010, osmotic swelling and dilution of hemoglobin lead to "ghost cell" formation. Further, many RBCs will lyse in dilute urine (especially alkaline urine) so that RBC excretion may be underestimated. Reagent strip analysis can be useful in dilute urine samples to detect hemoglobin released from lysed erythrocytes.

Noting the timing of hematuria can be a practical means of initially localizing 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 urethra. 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.

Figure 1. 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.

Exercise-associated hematuria

Exercise is accompanied by increased filtration of RBCs and protein across the glomerular barrier in a high percentage of human and equine athletes. Typically, hematuria is microscopic but occasionally gross discoloration of urine may be observed. Gross hematuria may more commonly be a consequence of bladder mucosal erosions that may be traumatically induced by the abdominal contents pounding the bladder against the pelvis during exercise. Detection of focal bladder erosions or ulcers with a contrecoup distribution and a history of emptying the bladder immediately prior to the exercise bout would be characteristic for this problem (Figure 1). A diagnosis of exercise-associated hematuria should be one of exclusion after diagnostic evaluation has ruled out more common causes of hematuria such as presence of a cystolith.

1 B

Urethral tears

Although a recognized cause of hemospermia in stallions, tears of the proximal urethra at the level of the ischial arch are a more recently described cause of hematuria in geldings. Since the defects are difficult to detect without use of high-resolution videoendoscopic equipment, it is likely that condition was misdiagnosed previously. Consequently, hematuria has also been attributed to urethritis or hemorrhage from "varicosities" of the urethral vasculature. Urethral tears 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, affected geldings have a series of urethral contractions resulting in squirts of bright red blood. Occasionally, a smaller amount of darker blood may be passed at the start of urination. In most instances, the condition does not appear painful or result in pollakiuria. Interestingly, the majority of affected geldings have been Quarter Horses, Paints, or Quarter Horse crosses which have been free of other complaints. Treatment with antibiotics for a suspected cystitis or urethritis has routinely been unsuccessful, although hematuria has resolved spontaneously in some cases.

Figure 2. Proximal urethral tears at the level of the ischial arch in geldings: lesions are outlined by the arrows (2 A, 2 B & 2 C) while the middle image shows hemorrhage into the urethral lumen immediately following urination.

Examination of affected horses is generally unremarkable. In comparison, horses with hematuria due to urolithiasis or neoplasms involving the distal urethra or penis are usually presented with additional complaints such as pollakiuria, a foul odor to the sheath, or presence of a mass in the sheath or 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 mid-stream or by bladder catheterization appear grossly normal. Urinalysis may have normal results or there may be an increased number of red blood cells 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 via 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 (Figure 2). With hematuria of several weeks duration, the lesion may appear as a fistula communicating with the vasculature of the corpus spongiosum penis (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 movements of the urethra.

2 B

Although the pathophysiology of this condition remains unclear, it is likely that the tear develops as a "blowout" of the corpus spongiosum penis into the urethral lumen. Contraction of the bulbospongiosus muscle during ejaculation causes increased 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 urination and the surrounding mucosa heals by formation of a fistula into the overlying vascular tissue. An anatomical predisposition in Quarter Horses and Paints has not been documented but could be speculated based on an apparent increased risk in this breed. Further, many affected geldings have a wider space between the hind limb muscles under the tail and frequently have a defect in the musculature on one side.

2 C

Since hematuria may resolve spontaneously in some affected geldings, no treatment may be initially required. If hematuria persists for more than a month or if significant anemia develops, a temporary subischial urethrotomy 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 corpus spongiosum penis but not into the urethral lumen to form a "pressure relief valve" or path of lower resistance for blood to exit the corpus spongiosum penis at the end of urination. The surgical wound requires a couple of weeks to heal and moderate hemorrhage from the corpus spongiosum penis 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 5-7 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, often life-threatening 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 3). 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, a wide age range, and several breeds of horses (including a mammoth donkey and a mule) have been affected. However, the majority of equids with IRH have been Arabians.

Figure 3. Urination in horses with idiopathic renal hematuria is accompanied by passage of blood clots (3 A) and cystoscopic examination usually reveals blood clots passed with urine from one of the ureteral orifices (3 B).

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. Benign 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 commonly a unilateral than a bilateral problem, similar to what has been observed in the few affected horses. Although hematuria and/or pigmenturia can accompany a number of systemic diseases in horses, 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 a consequence of pyelonephritis, supportive data was lacking. In affected Arabian horses managed by the author, neither UTI nor lithiasis has been detected and the magnitude of hematuria often 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, renal colic has been notably absent in the history of affected horses.

3 B

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 due to 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. Repeated examinations may be required to answer the latter question. Ultrasonographic imaging is necessary to rule out nephrolithiasis, ureterolithiasis, or a vascular anomaly as the cause of hematuria, With IRH, renal ultrasonographic findings may be normal or the renal pelvis of the affected kidney may be distended with blood clots.

Treatment for IRH consists of supportive care for acute blood loss, possibly including blood transfusions. Medications intended to promote hemostasis (α-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 but owners should be warned that there is a risk of hematuria developing in the contralateral kidney. In the author's experience, risk of contralateral renal bleeding appears to be greater in the Arabian breed. Anecdotally, hemorrhage has stopped in conjunction with administration of corticosteroids (dexamethasone, 0.1-0.2 mg]kg, q 24 h for 3-5 d) so this treatment can be considered prior to pursuing a nephrectomy or euthanasia.

Supplemental readings available on request to the author