The diagnostic approach to hematuria

Hematuria can be undetectable on gross examination of urine samples, or the red blood cells (RBCs) can impart a variety of colors to urine and must be distinguished from other components that discolor urine. Hematuria is a common finding in dogs and cats, but identifying the source can be difficult since RBCs can be introduced anywhere along the urinary tract and may arise from the genital tract as well. Underlying causes of hematuria range from iatrogenic sources such as sample collection technique to disorders that produce marked morbidity. This article and the accompanying algorithms are intended to guide practitioners through the series of steps necessary to confirm the presence of hematuria, localize the source of the RBCs, and identify the specific cause.

STEP 1: CONFIRM THE HEMATURIA

Depending on the degree of hematuria, urine can range from a relatively normal yellow-to-amber color to abnormal red, orange, or brown shades. Thus, RBCs may be detected incidentally when you evaluate urine as a part of a routine health examination or discovered when you examine urine as part of a work-up in patients with a variety of clinical signs. Distinguishing substances other than RBCs as a source of urine discoloration is an important first step in correctly identifying and pursuing patient problems (Figure 1).

Figure 1

Dipstick colorimetric testing is a readily available, economic way to identify blood in urine, but keep in mind that a positive result is not specific for intact RBCs but is also compatible with hemoglobinuria or myoglobinuria. And regardless of pigment type, grossly discolored urine can make accurate interpretation of dipstick test pads difficult.

Estimate the number of RBCs

If the dipstick test result is positive for blood, examine the urine sediment to confirm RBCs and to approximate their number. A small number of RBCs is normal depending on the case and the urine collection method. Voided urine samples may normally have 0 to 8 RBCs/HPF, catheterized samples may normally have 0 to 5 RBCs/HPF, and cystocentesis samples may normally have 0 to 3 RBCs/HPF.1,2 While these numbers may seem counterintuitive, keep in mind that some cystocentesis and catheterized samples may be more difficult to obtain than others, and the degree of potential trauma or contamination during collection must be taken into account when excessive RBCs are present in urine samples obtained by any of these methods. Conversely, if RBCs are absent or relatively lacking in a urine sample obtained by cystocentesis or catheterization when compared with a voided sample, suspect a genital or urethral source of hematuria.

Rule out hemoglobinuria and myoglobinuria

In the absence of a marked number of RBCs in a urine sample that had a positive dipstick test result for blood, rule out hemoglobinuria and myoglobinuria by inspecting the patient's plasma. Pink plasma supports hemoglobinuria, while clear plasma is compatible with myoglobinuria or RBC lysis in the urine before sediment examination. Myoglobinuria may be confirmed with an ammonium sulfate test at a commercial laboratory.

Rule out bilirubinuria

If the result for blood on a dipstick is negative and the result for bilirubin is positive, bilirubinuria most likely accounts for the urine discoloration. The greater the quantity of bilirubin present in the urine, the more likely that discoloration will result. The clinical relevance of bilirubinuria is a separate issue and depends on the patient's urine specific gravity, species, and sex. Any amount of bilirubin in a cat's urine is considered abnormal. Urine with < 1+ bilirubin and a specific gravity ≥ 1.020 is generally considered normal for male and female dogs. Male dogs may normally have up to a 1+ bilirubin reading in concentrated urine. Urine with a bilirubin ≥ 1+ and a specific gravity ≥ 1.020 is a potentially clinically relevant finding, especially in female dogs. Canine urine with a bilirubin > 1+ and a specific gravity < 1.020 is clinically relevant regardless of sex.3

Check for pseudohematuria

A negative urine dipstick result for blood with a concurrent negative result for bilirubin from a patient with discolored urine warrants testing a second urine sample in case RBCs are only intermittently present. If the second sample's dipstick or sediment examination results remain negative for RBCs, consider pseudohematuria—urine discoloration from pigments derived from drugs such as doxorubicin, food dyes, toxins such as mercury, or inherited conditions such as porphyria—and review the patient's historical and physical examination findings.4 If you suspect pseudohematuria, persistent discoloration of urine supernatant after centrifugation may provide further evidence of this condition. If you cannot find evidence of an abnormal exogenous or endogenous pigment resulting in discoloration, it is possible that the color is a normal manifestation of urochrome and urobilin (normal urine pigments) in a concentrated urine sample. In this instance, the urine typically has a dark-yellow to brown hue.

In rare instances, abnormal pigment in urine cannot be identified by standard evaluation methods and, if persistent, could be pursued by expanded laboratory testing. State veterinary diagnostic laboratories are good resources for investigating the possible presence of toxins, dyes, medications, and porphyrins. In addition, PennGen, the Section of Medical Genetics associated with the University of Pennsylvania School of Veterinary Medicine, may be able to provide guidance in detecting inherited disorders of heme synthesis in young patients.

STEP 2: RE-EVALUATE HISTORICAL AND PHYSICAL EXAMINATION FINDINGS

A thorough history and physical examination often play important roles in identifying hematuria as a potential problem and localizing the source of hematuria (Figure 2). Obtain the patient's reproductive history and, in intact females, estrous cycle information as part of a complete history. Ask the owner about the possibility of trauma to the pet, including whether the pet has a history of recent vigorous exercise prior to the observation of discolored urine.

Figure 2

Note clinical signs, history, and variations in hematuria based on the collection method

Identifying signs of systemic disease, urination frequency, and dysuria can help establish whether the hematuria more likely originates from the upper urinary tract, lower urinary tract, or genital tract. Classic signs of lower urinary tract disease include pollakiuria and dysuria. Signs of systemic disease such as weight loss or fever support upper urinary tract or, in some cases, genital tract disease.

Difficult defecation in male dogs may indicate prostatic disease. A patient's medication history or its potential exposure to toxins may signal hematuria related to a coagulopathy or originating from the upper urinary tract. Determining whether the owner has seen evidence of bleeding unrelated to the urinary tract may also connect hematuria to a coagulopathy. Suspect a coagulopathy if the physical examination reveals bleeding from another organ system, including petechiation or ecchymoses of the skin. Perform a fundic examination not only to determine evidence of infectious or neoplastic disease but also to look for retinal hemorrhage that could indicate a coagulopathy.

Figure 3

Although systemic hypertension is not generally considered a primary cause of hematuria, its presence is often associated with renal disease and could exacerbate bleeding and alter treatment. Historical and physical findings that may indicate systemic hypertension include polydipsia and polyuria; cardiac murmur; tachycardia; epistaxis; neurologic signs such as disorientation, ataxia, or seizures; and ocular abnormalities such as choroidopathy, retinopathy, and hemorrhage.

When blood is observed grossly in a voided sample but is not as readily apparent in urine obtained by cystocentesis or catheterization, suspect a genital or urethral source of hematuria. However, hematuria from a genital tract or urethral source can sometimes be observed in both voided and nonvoided samples since the collection technique can result in iatrogenic RBC contamination or because material from the genital tract or urethra may reflux into the bladder, especially in patients with prostatic disease.

Examine the urogenital area and observe voiding

During the physical examination, be sure to inspect the genitalia and urethral orifice as well as to abdominally palpate the bladder, kidneys, and prostate. Although sometimes involved in disorders resulting in hematuria, the uterus is generally not palpable in intact female dogs unless it is enlarged or associated with a mass. If the bladder is markedly distended with urine when palpated, palpate it again after the animal has voided to increase the chances of palpating abnormalities in the bladder wall or lumen. Extrude the penis from the prepuce for inspection in male patients, and include digital palpation of the perineal urethra as part of the urogenital examination. Vaginal examination can be enhanced by using a speculum or digital palpation. Rectal palpation allows the opportunity to palpate the prostate in male dogs, the pelvic urethra in most patients, and the posterior aspect of the bladder in some patients. Identifying pain or irregularities during palpation may indicate that organ or structure as a source of hematuria.

Observe the patient during voiding to help verify hematuria and to confirm or detect abnormalities such as dysuria that could localize the source of hematuria. The stage of micturition at which blood appears can also help you localize the origin of hematuria. However, only general guidelines can be given since the stage of micturition when blood is observed often varies for any one source of hematuria. Blood seen at the beginning of urination or dripping independent of urination suggests a genital or urethral source. Blood produced at the end of urination often indicates a urinary bladder origin. Blood that persists throughout micturition is more suggestive of a kidney or ureteral origin, although a bladder origin cannot be ruled out. Urethral catheterization may be indicated in some cases, especially to assess patency in dogs or cats in which dysuria has been observed or reported.

Figure 4

STEP 3: PERFORM OR RE-EVALUATE DIAGNOSTIC TESTS

After localizing the source of hematuria based on historical and physical examination findings, follow the most appropriate algorithm (Figures 3-7) to devise a diagnostic plan to identify the specific cause of hematuria.

CBC and serum chemistry profile

Performing a CBC and a serum chemistry profile is never inappropriate in patients with hematuria. However, these tests are particularly indicated in patients with systemic signs of illness; palpable abnormalities in one or both kidneys, the uterus, or the prostate; or evidence of concurrent disease. Pay particular attention to the platelet count or platelet estimate, the RBC count, and the blood urea nitrogen and creatinine concentrations. A markedly low platelet count may indicate a coagulopathy. Anemia may indicate a more severe or persistent cause of hematuria and may affect therapy. Azotemia may implicate the kidney as a source of hematuria and complicate diagnosis and treatment, especially if anesthesia or other procedures that could compromise kidney function are required.

Figure 5

Urinalysis

Urinalysis is an essential part of evaluating hematuria, regardless of the source. Always consider the method of urine collection and the urine specific gravity when evaluating urinalysis results. Urinalysis is best performed within 30 minutes of sample collection. A longer delay can result in cellular deterioration, pH changes, bacterial growth, and precipitates that can be confused with crystals.5 Refrigerate urine samples that cannot be examined within 30 minutes of collection, but gradually warm them to room temperature to obtain accurate dipstick chemical analysis.

In most cases, obtaining urine by cystocentesis is desirable to avoid genital and environmental contamination. When a coagulopathy is suspected, cystocentesis should only be cautiously attempted because of the possibility of causing excessive bleeding. When hematuria is suspected to be of genital or urethral origin, comparing urinalysis results from a voided sample with results from a cystocentesis sample may provide evidence of a genital or urethral source.

Urine chemical and sediment examination. Urine chemical and sediment findings such as protein, infectious organisms, white blood cells, casts, and crystals can help determine definitive or contributing causes of hematuria. Always assess the clinical relevance of these findings in relationship to the urine collection technique and the total clinical evaluation of the patient. For example, crystals can be a normal finding in urine samples and are not considered a cause of hematuria, although their presence may be associated with potential sources of hematuria such as uroliths.

If you suspect a lower urinary tract infection (UTI), it is reasonable to try to eradicate the infection in an attempt to resolve the hematuria. Ideally, treat bacterial infections by selecting antibiotics based on bacterial culture and antimicrobial sensitivity testing results. Treat patients with multiple episodes of UTIs, systemic signs of illness, systemic fungal infections, genital tract infections, or upper UTIs with longer courses of antimicrobial drugs. These patients should undergo further diagnostic procedures to identify complicating factors and other organ system involvement. If parasites are identified in urine, such as Capillaria or Dioctophyma species ova or Dirofilaria species microfilariae, administer an appropriate parasiticide. In patients with Dioctophyma or Dirofilaria species infections, perform additional diagnostic procedures before treatment to assess kidney function and structure as well as other organs that might be affected by these parasites.

Blood pressure measurement

Routine screening for systemic hypertension by performing blood pressure measurements is advisable if you suspect upper urinary tract disorders or in cases in which localizing the source of hematuria cannot be reasonably accomplished through historical and physical examination findings.

Coagulation profile

Coagulopathy-related hematuria is more likely to be caused by a primary hemostatic defect involving platelets rather than secondary hemostatic clotting factor defects. Consequently, consider evaluating von Willebrand's factor activity and platelet function if the initial coagulation profile (Figure 6) is unremarkable or inconclusive. When a coagulopathy is identified, it is advisable to find the location of bleeding from the urogenital tract and to rule out any concurrent urogenital disease that might be exacerbating the patient's bleeding tendencies.

Figure 6

Diagnostic imaging

Diagnostic imaging plays an important role in tracking down the site and cause of hematuria. Abdominal radiography and ultrasonography are usually indicated in cases of hematuria. Imaging is indicated early in the diagnostic process in patients with a recent history of trauma or physical examination findings such as abdominal masses or abnormalities associated with a kidney, the bladder, the uterus, or the prostate. Use imaging to thoroughly examine the urogenital tract for irregularities, including masses, abnormalities in the shape and size of structures, and uroliths or bladder sediment.

Although blind aspirates and biopsies of suspicious areas of the urogenital tract can be performed, ultrasonography provides a potentially safer, more accurate method of obtaining samples for cytologic or histologic examination or culture. In patients with lower urinary tract signs, a retrograde contrast study may be indicated to identify urethral abnormalities, further evaluate bladder masses, and recognize radiolucent calculi. Patients with evidence of upper urinary tract disease or hematuria that has yet to be localized may be candidates for an excretory urogram to identify functional or subtler structural abnormalities. To avoid introducing bacteria or other contaminants, collect samples from the urogenital tract for bacterial culture or other analysis before performing contrast procedures. Advanced imaging such as computed tomography or magnetic resonance imaging may be indicated when the results of traditional imaging methods are inconclusive.

Cystourethroscopy

Cystourethroscopy is becoming more popular for diagnosing hematuria-related disorders. Although equipment availability, the patient's size, and the need for sedation or anesthesia can be limiting factors, lower urinary tract endoscopy allows localization of the source of hematuria, direct visualization of lesions, the opportunity to biopsy lesions with less chance of seeding neoplastic cells, and therapeutic options such as lithotripsy.

Figure 7

Endoscopy provides an excellent method of establishing one or both kidneys as the source of hematuria by enabling visualization of blood-tinged urine flowing from the ureteral openings into the bladder (Figure 8). Rigid endoscopy allows visualization of the bladder and urethra in patients weighing > 6.6 lb (3 kg) and < 44 lb (20 kg), including female dogs and cats and male cats that have undergone perineal urethrostomy. Flexible endoscopes allow examination of the lower urinary tract in most dogs and cats regardless of size or sex.6,7

Figure 8. Note the blood-tinged urine emerging from the ureter opening (arrow) into the bladder as visualized on cystoscopy.

Abdominal exploratory

If less-invasive diagnostic tests have not revealed the source of the hematuria, abdominal exploratory surgery may be indicated. An exploratory not only allows gross examination and biopsy of the urogenital system, the ureters can be catheterized individually to determine whether blood is present in the urine produced by one or both kidneys.

Before performing biopsies or exploratory surgery in patients with hematuria, perform a coagulation profile to establish that excessive bleeding is unlikely to occur. An activated clotting time could be used as a screening test, but it is not as sensitive of an indicator of bleeding potential as are the prothrombin time, partial thromboplastin time, and platelet count included in a standard coagulation profile.

STEP 4: PINPOINT THE CAUSE BASED ON DIAGNOSTIC TEST RESULTS

Table 1 summarizes possible causes of hematuria based on potential outcomes of the diagnostic algorithms for suspected urogenital sources.

Table 1: Causes of Hematuria Based on Algorithm Findings and Localization of Urogenital Source

Exercise-induced hematuria may represent a rare subcategory of trauma that is diagnosed by excluding other causes of hematuria and noting a history of vigorous exercise that occurred within minutes to a few days before blood became apparent in the urine.8,9 Exercise-induced hematuria, as described in people, is transient and is thought to be primarily related to bladder mucosal damage that occurs as a result of repetitive or vigorous movement of the bladder during exercise. In some cases, the source of exercise-induced hematuria may be nontraumatic and occur as a result of increased glomerular excretion of RBCs into the urine.10,11

Although uncommon, leakage of RBCs through the glomerulus can occur because of chronic congestive mechanisms resulting from disorders such as heart failure8,12 or as a consequence of ischemic and congestive mechanisms associated with exercise-induced hematuria.11

Renal hematuria can fall in an idiopathic category. Primary (idiopathic) renal hematuria is thought to result from benign vascular abnormalities that are not readily recognizable through typical diagnostic procedures.13-15

SUMMARY

Handling patients with hematuria begins with confirming RBCs in the urine since a variety of pigmented substances can discolor the urine. Hematuria can be confused with hemoglobinuria, myoglobinuria, bilirubinuria, and pseudohematuria. Once RBCs have been confirmed, historical and physical examination findings can often localize the source of hematuria to the upper urinary tract, lower urinary tract, or genital tract. Coagulopathies must be differentiated from disease of the urogenital tract as the source of urine RBCs. After localizing the source of hematuria, you can follow a series of algorithmic steps delineating a logical diagnostic plan to identify categories of disorders that can lead to a specific cause of hematuria.

Mary Bowles, DVM, DACVIM

Department of Veterinary Clinical Sciences

Center for Veterinary Health Sciences

Oklahoma State University

Stillwater, OK 74078

REFERENCES

1. DiBartola SP. Renal disease: clinical approach and laboratory evaluation. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 6th ed. St. Louis, Mo: Elsevier, 2005;1716-1730.

2. Chew DJ, DiBartola SP. Urinalysis interpretation. In: Interpretation of canine and feline urinalysis. Wilmington, Del: The Gloyd Group Inc, 1998;15-33.

3. Davies C, Shell L. Discolored urine. In: Common small animal diagnoses: an algorithmic approach. Philadelphia, Pa: Saunders, 2002;200-201.

4. Bartges JW. Discolored urine. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 6th ed. St. Louis, Mo: Elsevier, 2005;112-114.

5. Chew DJ, DiBartola SP. Sample handling, preparation, and analysis. In: Interpretation of canine and feline urinalysis. Wilmington, Del: The Gloyd Group Inc, 1998;9-11.

6. McCarthy TC. Lower urinary tract endoscopy, in Proceedings. Western Vet Conf 2002.

7. Chew DJ, McLoughlin MA, Cannizzo K. Uroendoscopy in dogs and cats, in Proceedings. Western Vet Conf 2003.

8. Kaufman GM. Hematuria-dysuria. In: Ettinger SJ, ed. Textbook of veterinary internal medicine. 3rd ed. Philadelphia, Pa: WB Saunders Co, 1989;160-164.

9. Grauer GF. Clinical manifestations of urinary disorders. In: Nelson RW, Couto CG, eds. Manual of small animal internal medicine. St. Louis, Mo: Elsevier Mosby, 2005;368-377.

10. Gambrell RC, Blount BW. Exercise–induced hematuria. Am Fam Physician 1996;53(3):905–911.

11. Arbarbanel J, Benet AE, Lask D, et al. Sports hematuria. J Urol 1990;143(5):887-890.

12. Lorenz MD. Discolored urine. In: Lorenz MD, Cornelius LM, eds. Small animal medical diagnosis. Philadelphia, Pa: JB Lippincott Co, 1987;331-342.

13. DiBartola SP. Renal disease: clinical approach and laboratory evaluation. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 6th ed. St. Louis, Mo: Elsevier, 2005;1716-1730.

14. Forrester SD. Diagnostic approach to hematuria in dogs and cats. Vet Clin North Am Small Anim Pract 2004;34(4):849-866.

15. Berent AC. Endourology and interventional radiology of the urinary tract, in Proceedings. Am Coll Vet Intern Med Forum 2007.