ABSTRACT: The presence of blood in the urine is a significant finding that calls for prompt evaluation. Gross hematuria usually indicates a serious problem; its correlation with malignancy-typically a transitional cell carcinoma-is fairly high. Microscopically detectable blood is less likely to signal a major underlying condition; a finding of 0 to 3 red cells per high-power field is probably innocent. The workup for gross and microscopic hematuria focuses on disturbances of urinary tract function and includes a history and physical examination, urinalysis, radiologic imaging, urine cytology, and cystoscopy. The presence of hematuria, proteinuria, and renal insufficiency warrants referral to a nephrologist. A search for the cause of microscopic hematuria is much less likely than a workup for gross hematuria to uncover a life-threatening condition. If the hematuria persists, repeat the urinalysis and cytology every 6 months until the problem resolves or 3 years have passed.
Urine should not contain any blood. This is the executive summary of this article. The practitioner summary might go like this: grossly bloody urine has a relatively high association with malignancy and microscopic hematuria does not.
Clearly, a finding of blood in the urine needs an explanation. Although most medical laboratories consider fewer than 3 red blood cells (RBCs) per high-power field in the urine as normal, there really should not be any blood-or for that matter, much of anything-in the urine.
What should you do when you find blood in your patient's urine? Unfortunately, there is no absolute answer to this question. The discussion that follows is a reminder that medicine is as much an art as it is a science. Judgment and instinct must be combined with laboratory data and clinical findings before a management plan can be developed.
Here I discuss how to organize the response to a finding of blood in the urine. Gross blood (visibly red urine) is an ominous discovery, and it needs a very solid explanation. Microscopically detectable blood is much less likely to indicate a dangerous problem, but it requires a similar evaluation.
FALSE JUDGMENT OF "URINE"
The inspection of voided urine has been part of the medical practitioner's modus operandi since probably forever. Hippocrates considered inspection of the urine useful for establishing a patient's prognosis. He noted, "A small quantity of blood passed without fever or pain does not indicate anything bad. . . . But if in large quantities with the addition of any of these symptoms it is to be dreaded."1 Inspection of the urine (uroscopy) was, in fact, so intrinsic to medical practice that during the Middle Ages, the container used to observe the urine, the Matula, became as much a symbol of medicine as the red and white striped pole is now a symbol of a barbershop.
As with some other medical tests that initially enjoyed great favor, uroscopy began to have more benefits attributed to it than it could deliver. By the end of the 14th century, charlatans made medical judgments based sole- ly on the urine-without seeing the patient at all. Petrus Forestus condemned this unscientific practice in his 1589 book, The False Judgment of Urines. A 16th-century lawyer, Jean Brèche, referred to uroscopists as "empirics, pests and mountebanks," and dubbed their victims "stupid, conceited simpletons and complete fools."1 One might guess that Brèche did not have many plaintiff clients!
Despite its checkered history, urinalysis remains one of the more commonly performed clinical tests. In my urology clinic, we often pay homage to our medical pioneers by holding the plastic urine specimen cup (our 21st-century Matula) up to the light to do some prognosticating of our own. Visible blood in the specimen hardens our resolve to insist on diagnostic cystoscopy, even when the patient tries to talk us out of it.
Hippocrates' observation regarding the prognostic significance of blood in the urine remains valid today. There is a direct relationship between the quantity of blood found in the urine and the likelihood of pathology.
But before you leap to conclusions, consider the quality of the collected data. For example, a common and innocent source of blood in the urine is menstruation. In addition, obese women and phimotic men often cannot provide a clean-catch specimen. If, during a physical examination, you need 2 hands to visualize the urethral meatus of a heavy woman and are unable to retract the foreskin of a phimotic man, one can only imagine what is happening when these patients attempt to provide a clean-catch specimen.
In short, consider the practicalities of a patient's ability to provide a truly clean-catch specimen before you place much stock in the urinalysis results. Insert a catheter to obtain a urine specimen if a clean midstream collection is not possible.
One of the more likely explanations for blood in the urine is bacterial cystitis. When blood and bacteria are found in a urine sample, the first step is to treat the infection. If no blood appears in subsequent specimens, you may think that you are done with the problem. But such is not the case: Read on!
In the real world, a bladder infection usually is treated empirically. The available antibiotics are up to the challenge posed by most of the organisms that attack the urinary tract. A urine culture is indicated for patients at increased risk for infection, such as those with a congenital urinary tract abnormality, a surgically or traumatically altered urinary tract anatomy, or a history of immune deficiency or those who have had a previous life-threatening urinary tract infection. The results of a urine culture are useful if the initial antibiotic fails and the patient's condition worsens. The antibiotic sensitivities from a urine culture give you something more concrete to rely on when choosing the "plan B" antibiotic.
Gross hematuria is indeed a red flag, and it makes me nervous. It is especially worrisome in a patient who has a long history of cigarette smoking. Such persons are at high risk for urinary tract neoplasm. Even if such a patient has a concomitant urinary tract infection, I would be hard-pressed not to pursue a thorough workup.
Patient evaluation. In the patient with gross hematuria, I specifically look for urinary tract function disturbances. I ask about urinary urgency, frequency, dysuria, and any history of urinary tract neoplasm or stones. Laboratory, imaging, and diagnostic studies include serum creatinine measurement, urinalysis, urine culture and cytology, CT, and an initial cystoscopic examination with local anesthesia.
The CT urogram has nearly supplanted the intravenous pyelogram in the evaluation of hematuria. A non-contrast CT scan of the abdomen and pelvis "stone run" followed by the same scan with the addition of intravenous contrast should identify nearly any pathology that you are likely to confront.2,3 An abdominal/renal ultrasound scan may be needed to further refine the characteristics of renal cysts noted on the CT scan, but it cannot, as a rule, be relied on as the sole imaging technology when evaluating hematuria.
If the imaging studies identify a suspicious mass within the ureter or renal collecting system or if cystoscopy reveals grossly bloody urine coming from a ureteral orifice, ureteroscopy may be helpful. Abnormal cytology in the absence of obvious bladder tumors may be an indication for more aggressive inspection/biopsy of the bladder, ureters, and renal collecting systems.
Neoplasms. A tumor that causes gross hematuria is usually a transitional cell carcinoma. Renal cell adenocarcinomas (hypernephromas) do bleed but much less frequently than transitional cell neoplasms-and usually such bleeding is a late manifestation of the tumor's growth. Transitional cell tumors generally form a fragile branched growth on the inner surface of the urinary tract (Figure) that bleeds fairly easily (gross hematuria). This is why transitional cell tumors are detectable at such an early, surgically curable stage. Most commonly found in the bladder, these tumors can grow anywhere on the transitional cell lining of the urinary tract.
Although bladder tumors are occasionally seen on the CT urogram, the majority are identified cystoscopically. Ureteral and renal collecting system tumors are a challenge to locate, but the urinary tract obstruction they create makes them somewhat easier to identify radiologically than bladder tumors. Increasingly, the ureteroscope is used to confirm the presence of ureteral and collecting systems tumors.
Because of its high false-negative rate, urine cytology alone is not a reliable means of evaluating hematuria. The transitional cells that comprise a low-grade transitional cell carcinoma do not appear particularly abnormal under the microscope. A papillary neoplasm (transitional cell carcinoma) is defined more by the appearance of the papillary growth than by the characteristics of its individual cells. Hence, we depend on direct visualization of tumors when evaluating hematuria: the urologist sees the papillary tumor growing on the urinary tract lining.
Cytology does help detect high-grade tumors. The cells of a high-grade transitional cell tumor appear abnormal on urine cytology and may not even form a papillary growth detectable by cystoscopy/ureteroscopy. Cytology also can aid in the discovery of tumors that are in the ureters or collecting systems of the kidneys-beyond the vision of the cystoscope. These potentially small tumors may be missed by the CT urogram. A suspicious-looking cytology finding may be the only clue that spurs the hematuria evaluation on when cystoscopy results are normal.4
Some promising bladder tumor assay tests are becoming available. Someday these tests may have sufficient sensitivity to simplify the evaluation of hematuria. Currently, the assays are most appropriately employed in the surveillance of patients with a history of bladder cancer. They all share the same lack of sensitivity that makes cytology unreliable for the diagnosis of low-grade papillary neoplasms.5
There is solid support in the literature for the need to aggressively investigate gross hematuria. Two reviews, one of hematuria evaluations in a Northern Ireland clinic (100 patients studied) and the other of an HMO serving 15% of the population of Hawaii (1000 patients studied) demonstrated that about 25% of the patients with gross hematuria had life-threatening lesions, most of which were transitional cell carcinomas.6-8
In the Northern Ireland study, Ho and colleagues7 found that 60% of patients sought medical care within 1 week of the onset of gross hematuria and 14% waited more than a month to see a physician. Only 32% of the patients were referred to a urologist within a week; it took more than 8 weeks for 14% of the patients to be evaluated.
Diagnostic delay of transitional cell cancer can be deadly. Most transitional cell carcinomas of the bladder can be detected when they are superficial tumors of the bladder lining. These tumors can be treated very effectively by transurethral resection. Although the rate of recurrence is fairly high (which necessitates repeated evaluations), the 5-year survival rate among patients with these superficial tumors approaches 95%.
Transitional cell tumors of the ureter and collecting system are not usually amenable to local resection, but they are also surgically curable when detected early enough. When left to their own devices, however, urothelial tumors can invade the deeper, muscular portions of the urinary tract wall, with disastrous consequences. The 5-year survival rate of patients with high-grade, deeply invasive tumors has been found to be as low as 31%. Once the tumor reaches lymph nodes, 5-year survival is unlikely. Although aggressive therapeutic regimens show promise for extending the survival of patients with metastatic transitional cell carcinoma, the outlook remains dismal.9
When a urology clinic fails to provide a timely appointment for your patient with gross hematuria, speak directly to the urologist. If you still cannot arrange for the patient to be seen within a week or so, find a new urologist.
Microscopic hematuria is anoth-er matter entirely, since it does not represent much of a threat. It remains the standard of care, however, to evaluate microscopic hematuria when it is discovered. In the Northern Ireland study, no malignancies were detected among the patients with microscopic hematuria.7 In the Hawaii study, however, 1.7% of the women and 6% of the men with microhematuria had a potentially life-threatening problem, although not all of them were neoplasms.8 In the Irish study, 73% of the evaluations failed to uncover the source of the hematuria.
Patient evaluation. My evaluation for microscopic hematuria is the same as for gross hematuria: a focused interview and physical examination looking for disturbances of urinary tract function. Laboratory, imaging, and diagnostic studies that consist of serum creatinine measurement, urinalysis, urine culture and cytology, CT urography, and cystoscopic examination with local anesthesia complete the evaluation. Cytologic evaluation of the urine may not be appropriate for all instances of microscopic hematuria, but few of my patients are excluded by the published exclusion criteria.10
"Normal hematuria." Although normal values of 0 to 3 RBCs per high-power field are seen commonly in the reference values of clinical laboratories, I believe that these numbers are not based on anything to do with renal anatomy. A paper by Addis11 published in 1926 reported that healthy persons excrete RBCs. Apparently, this is at least part of the reason for the concept of "normal" hematuria. But it seems unlikely that this "normal" hematuria could be of glomerular origin, since glomerular filtration slits are a fraction of the diameter of an RBC (Box).
The trauma of daily physical activities, which is capable of producing urinary tract bleeding, is probably one source of "normal" hematuria.
Microscopic hematuria accompanied by significant proteinuria is a sign of renal disease. Dysmorphic RBCs or RBC casts with or without proteinuria also are signs of renal disease. Blood alone in the urine will not produce measurable proteinuria.
LOOKING FOR TROUBLE?
All of this said, I feel compelled to evaluate persons with microscopic hematuria, searching for the elusive life-threatening condition. The "normal" level of 0 to 3 RBCs per high-power field seems well accepted as an exclusionary criterion, but the fear remains that microscopic hematuria may be the only sign of urothelial neoplasm.
Consider the age and habits of the patient when you respond to the discovery of microscopic hematuria. When seen in a heavy smoker, even a little hematuria should sound an alarm. I am also concerned when a patient with very poor eyesight confidently denies gross hematuria. On the other hand, I am willing to hold aggressive evaluation in abeyance and observe a healthy nonsmoking patient who is younger than 40 years, if he or she is comfortable with this approach.
The Hawaiian study6,8 used the following very reasonable criteria for hematuria evaluation:
Patients with 3 or more RBCs per high-power field on at least 2 of 3 properly collected specimens and properly performed urinalyses or those who have had a single episode of high-grade (greater than 100 RBCs per high-power field) microscopic or gross hematuria should be evaluated.
There must be no urinary tract instrumentation or vigorous exercise during the 48 hours immediately before the urinalysis.
Women should not be menstruating.
Patients with 2+ proteinuria in addition to the hematuria should be evaluated for glomerular disease.
Mariani,6 author of the Hawaiian study, noted that no tumors were discovered in patients excluded by these criteria. He cautions-and I concur-that despite this reasoned guideline, clinicians must maintain a high level of suspicion, since there really should never be any blood in the urine. (There is, after all, a snake under every rock!)
THE END GAME
Actually, one of the more vexing problems related to hematuria evaluation is how to stop the evaluation process. Perhaps you have a patient who has an innocent, but unfortunately persistent, form of microscopic hematuria. It is entirely reasonable to wonder, when the hematuria is unchanged after 6 months, "now what?"
Hematuria evaluations appear to have a relatively low false-negative rate. I generally repeat the urinalysis and cytologic examination every 6 months until the hematuria resolves or approximately 3 years have passed. If any suspicious cells are noted in the cytology specimens or the hematuria worsens, I repeat the initial evaluation.
Mariani6 also has used the same approach without a single failure to diagnose urinary tract neoplasm. The natural history of papillary neoplasms-the primary threat when hematuria is discovered-supports this approach. Transitional cell carcinoma of the urinary tract does not give you 3 years to ponder its existence. n
1. Murphy JTL, Desnos E. History of Urology. Springfield, Ill: Thomas; 1972.
2. Amis ES Jr. Epitaph for the urogram. Radiology. December 1999;213:639-640.
3. O'Malley ME, Hahn PF, Yoder IC, et al. Comparison of excretory phase, helical computed tomography with intravenous urography in patients with painless haematuria. Clin Radiol. 2003;58:294-300.
4. Hofland CA, MarianiAJ.Is cytology required for
a hematuria evaluation? J Urol. 2004;171:324-326.
5. Halling KC, King W, Sokolova IA, et al.A comparison of BTA stat, hemoglobin dipstick, telomerase and Vysis UroVysion assays for the detection of urothelial carcinoma in urine. J Urol. 2002;167:2001-2006.
6. Mariani AJ. The evaluation of adult hematuria: a clinical update. AUA Update Ser. 1998;17.
7. Ho ET, Johnston SR, Keane PF. The haematuria clinic-referral patterns in Northern Ireland. Ulster Med J. 1998;67:25-28.
8. Mariani AJ, Mariani MC, Macchioni C, et al. The significance of adult hematuria: 1,000 hematuria evaluations including a risk-benefit and cost-effectiveness analysis. J Urol. 1989;141:350-355.
9. Ries LAG, Eisner MP, Kosary CL, et al, eds. SEER Cancer Statistics Review, 1975-2000. Bethesda, Md: National Cancer Institute; 2003. Available at: http://seer.cancer.gov/csr/1975_2000. Accessed April 14, 2004.
10. Grossfeld GD, Litwin MS, Wolf JS, et al. Asymptomatic microscopic hematuria in adults: summary of the AUA best practice policy recommendations. Urology. 2001;57:599-603.
11. Addis T. The number of formed elements in the urinary sediment of normal individuals. J Clin Invest. 1926;2:409.