David A. Spector
Normal individuals excrete up to 2 million red blood cells (RBCs) into the urine daily; this is equivalent to one to three RBCs per high-powered microscopic field (HPF) with standard urinalysis techniques. The finding of greater numbers of RBCs in the urine constitutes abnormal hematuria, although the exact level separating normal from abnormal is arbitrary. Benzidine- or orthotolidine-impregnated, hemoglobin-sensitive dipsticks, widely used as screening tests for hemoglobinuria (usually caused by lysis of RBCs in the urine and therefore an indication of hematuria), are less sensitive than microscopy but are usually positive in urine that contains at least three RBCs per HPF. The rate at which RBCs lyse depends on the concentration of the urine in which they are found and the duration of time they are exposed. Usually some lysis occurs within a few minutes, especially when the urine is dilute. There are certain limits to the use of hemoglobin-sensitive dipsticks (Table 49.1).
Microscopic hematuria may or may not indicate serious genitourinary tract disease (1,2). The symptoms, signs, and laboratory findings associated with hematuria and the clinical setting in which it occurs help considerably in predicting the seriousness of the finding. For example, gross hematuria or hematuria associated with proteinuria or pyuria is highly predictive of a significant disease. Conversely, asymptomatic microhematuria in a young adult has little predictive value.
Pseudohematuria
A large number of substances can impart a color to urine that may be mistaken for hematuria (3). Table 49.2 lists exogenous sources of some of these substances. Endogenous substances capable of producing a reddish hue include porphyrins, myoglobin, and hemoglobin. Myoglobin and hemoglobin also cause positive reactions in tests for RBCs. When the urine dipstick is positive and the microscopy is negative for RBCs, myoglobinuria or hemoglobinuria should be suspected. Both are serious findings and warrant further evaluation. Myoglobinuria indicates substantial muscle disease or injury, and hemoglobinuria indicates significant hematuria (with lysis of RBCs) or hemolysis. However, the dipstick reaction will be falsely positive in the presence of oxidizing substances (e.g., if there is heavy hypochlorite [bleach, chlorine] or peroxidase [from bacteria] contamination of the urine specimen or its container). A false-negative dipstick test may also occur when formaldehyde (e.g., present as a breakdown product of the antibacterial agent methenamine) or large amounts of vitamin C are in the urine, because both substances decrease the sensitivity of the test reagent.
Innocent Hematuria
Microscopic hematuria is sometimes identified after sexual activity or after a genitourinary tract examination such as a pelvic or prostate examination, cystoscopy or bladder catheterization, or biopsy of prostate, bladder, or kidney.
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Occasionally, gross hematuria may be seen in this setting. Gross or microscopic hematuria is also sometimes present after vigorous exercise such as swimming, lacrosse, boxing, football, or running. This finding is most common in long-distance runners, and in one study, 18% of athletes were found to have hematuria (mostly microscopic hematuria) after the completion of a marathon (4). Hematuria in all such settings subsides in 24 to 48 hours. It does not signify underlying genitourinary disease if it resolves quickly and does not recur spontaneously. In exercisers (especially runners), proteinuria or cast formation sometimes accompanies the hematuria, and the red cells have been found to be dysmorphic, suggesting that the bleeding site is the glomerulus.
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TABLE 49.1 Limits of Dipstick Method for Detection of Blood in the Urine |
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TABLE 49.2 Exogenous Substances That May Cause Pseudohematuriaa |
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Hematuria with Pyuria
If a patient is found to have hematuria associated with pyuria (with or without irritative symptoms such as frequency, urgency, or dysuria), an infectious cause is most likely and bacterial cultures of the urine should be obtained. If a specific organism is identified, appropriate antimicrobial therapy should be given (see Chapter 36). After treatment, the patient should be monitored carefully (including urinalysis) in 4 to 6 weeks to ensure that the hematuria has been eradicated and does not recur. If irritative symptoms suggesting infection have been present and the routine culture is sterile, a sexually transmitted disease (STD) (especially Chlamydia infection or gonorrhea), a viral infection, or genitourinary tuberculosis (now a rare cause of hematuria) should be suspected. In particular, Chlamydia trachomatis infection (see Chapters 36 and 102) may be manifested by hematuria and pyuria with minimal irritative symptoms. When a sexually transmitted infection is suspected but cannot be proved, a therapeutic trial of an antimicrobial drug may be given (see Chapters 36 and 102). Viral cystitis is a fairly common infection of young women. It has a short natural course (2 to 3 days), and it is nonrecurrent. A diagnosis oftuberculosis of the urinary tract requires several weeks to confirm by culture. (An acid-fast stain of a voided specimen of urine is not a reliable indicator because of the regular presence of acid-fast material from smegma bacilli. These bacilli would not be observed in a catheterized urine specimen, but most experts suggest simply waiting for the culture results in the typical patient in whom tuberculosis is a consideration.) Rarely, one may encounter a patient who is from an area endemic for schistosomiasis, and in this situation, the presence of hematuria should raise a question of this infection. Because noninfectious disorders of the bladder (including malignancies) may also present with irritative symptoms (see Chapter 53), one should ensure that those symptoms have abated after treatment, especially in patients older than 50 years of age, and it is probably prudent to confirm that the patient's urinalysis is normal 4 to 6 weeks after completion of treatment for an infection.
Hematuria with Proteinuria, Red Blood Cell Casts, or Dysmorphic Red Blood Cells
Hematuria associated with proteinuria reflects glomerulonephritis or, less often, interstitial nephritis. When proteinuria is greater than 2 g in 24 hours or RBC casts are present, the diagnosis is probably glomerulonephritis (see Chapter 48). The morphologic appearance on microscopy of the RBCs may help differentiate glomerular from nonglomerular bleeding (5). This observation takes advantage of the deformation of RBCs after their passage into the Bowman space. If more than 80% of at least 100 (counted) RBCs appear dysmorphic (abnormal size, shape, and cytoplasmic staining) by Wright stain (or phase contrast microscopy, if available) of the urinary sediment, glomerular bleeding is very likely. In particular, acanthocytes (RBCs with spiny projections), when present, almost always indicate glomerular disease (6). If glomerulonephritis is suspected, estimation of the glomerular filtration rate and measurement of 24-hour urine protein excretion are indicated. Even if proteinuria if not present, when glomerulonephritis is suspected a test for microalbuminuria might also be indicated since, when present
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in adults with microscopic hematuria, microalbuminuria is predictive of glomerular disease and especially of immunoglobulin A (IgA) nephropathy (Berger disease) (7). Chapter 48 suggests an approach to the patient with suspected glomerulonephritis. Although any form of glomerulonephritis may be present in a patient in whom hematuria is an incidental finding, either IgA nephropathy (8), Alport syndrome (hereditary nephritis, often associated with deafness), or thin basement membrane disease is especially likely. IgA nephropathy and Alport syndrome, in particular, are characterized by recurrent episodes of gross hematuria, dysmorphic red cells, microalbuminuria and/or proteinuria, and a progressive course. A nephrologist should be consulted when these or other forms of glomerulonephritis are suspected. Often the nephrologist will perform a renal biopsy (see Chapter 48) to establish the diagnosis, estimate the prognosis, and determine treatment.
Asymptomatic Isolated Microhematuria
The prevalence of isolated microscopic hematuria depends on the stringency of the diagnostic criteria (e.g., number of RBCs per HPF, number of “positive” tests required) and the population studied. For example, in each of five studies of young adults, less then 1% of the study population had asymptomatic hematuria (9). In contrast, asymptomatic hematuria was observed in 13% to 21% of older men who were considered to be at high risk for genitourinary carcinoma and other chronic urinary tract diseases (10).
Causes of Asymptomatic Hematuria
Most series describing the causes of microscopic hematuria come from the urology-oriented literature and emphasize diagnoses likely to be made by cystoscopic and radiographic evaluation (Table 49.3). Generally, neoplasia is more commonly reported in series comprising older individuals or patients referred to urologists; conversely, neoplasia is rarely found in population-based series of young patients.
In all series, no specific diagnosis was made for many patients, in part because patient evaluations were usually incomplete. For example, most series did not include a renal biopsy, which may have revealed glomerular or interstitial disease (11,12). The importance of this omission was borne out by one study in which 51 of 65 adult patients with hematuria with minimal or no proteinuria and a negative urologic workup had a specific diagnosis established only after the performance of a renal biopsy (11).
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Renal biopsy, when performed, often reveals a glomerular cause of hematuria in younger patients in whom the workup is otherwise unrevealing, and it also may reveal glomerular lesions in up to 40% of cases, even in elderly patients (12). As in patients with combined hematuria and proteinuria, the most likely biopsy findings in patients with asymptomatic hematuria are IgA nephritis, followed by Alport disease and thin basement membrane disease (12).
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TABLE 49.3 Distribution (%) of Selected Urologic Findings in Asymptomatic Patients with Microhematuria |
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TABLE 49.4 Causes of Hematuria |
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Additionally, most series did not include quantitation of 24-hour urine calcium and uric acid. Hypercalciuria (more than 300 milligrams per 24 hours) or hyperuricosuria (more than 750 mg/24 hours in women; more than 800 mg/24 hours in men) has been shown to cause hematuria (presumably as a result of irritation of the tubules by microcrystals), and thiazide therapy (which reduces calciuria) or allopurinol stops the bleeding in these circumstances (13). Table 49.4 shows a more complete listing of causes of hematuria.
Evaluation of Patients with Hematuria
Pseudohematuria and drug-induced hematuria (Table 49.5) should be ruled out. The evaluation then depends on associated symptoms, on whether the bleeding is gross or microscopic, and on the results of the complete urinalysis (discussed earlier). Localization of the site of the bleeding in the genitourinary tract is the first priority. The associated symptoms and the history of temporal events often provide diagnostic clues. For example, colicky flank pain suggests that the hematuria is emanating from the ureter, whereas dysuria and urinary frequency suggest that the bleeding is from the bladder. All patients should be asked about the temporal relationship of the hematuria to exercise, to ingestion of medications or food, and to trauma. The urinalysis is helpful also if findings suggest glomerular disease or infection (see earlier discussion). In some studies, the seriousness of the underlying lesion was proportional to the number of RBCs per HPF, and patients with gross hematuria were especially at risk for serious or life-threatening illness (14,15).
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TABLE 49.5 Examples of Drugs Causing Hematuria |
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A focused history and physical examination should be performed to seek clues to illnesses with which hematuria is associated (e.g., a nodular prostate suggestive of prostate cancer, cutaneous or other abnormalities suggestive of a collagen vascular disease). When the history and physical examination, together with selected laboratory procedures (e.g., urine culture) and treatment (e.g., antimicrobial agents), do not support a working diagnosis, certain laboratory data should be obtained. This evaluation should include a complete blood count (CBC), an
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estimate of glomerular function (e.g., serum creatinine), a sickle-cell preparation (in the appropriate patient), a 24-hour urine specimen for determination of calcium and uric acid concentrations (see earlier discussion), and a radiologic evaluation. The optimal radiologic procedure(s) for patients presenting with hematuria is not clear. Intravenous pyelography (IVP) has historically been the procedure of choice, with ultrasonography suggested for pregnant women or for those allergic to contrast dye. Although IVP is still recommended as best practice policy by the American Urologic Association (10), multiphasic helical computed tomography (CT) is generally more sensitive than IVP or ultrasonography in detecting small renal calculi (unenhanced CT) (16) and small renal masses (unenhanced CT followed by contrast-enhanced CT), and is specifically more efficacious than IVP in patients presenting with microscopic hematuria (17). Therefore some authors now suggest using helical CT urography without and with contrast as the initial procedure of choice in the evaluation of hematuria (Cohen and Brown; Steele and Michaels, http://www.hopkinsbayview.org/PAMreferences). In patients with a suspected bleeding disorder, a platelet count and measurement of the prothrombin, partial thromboplastin, and bleeding times should be done. Even if an underlying bleeding diathesis is identified, the search for a pathologic process in the genitourinary tract should continue, because one is usually identified (seeChapter 56). In patients older than 40 to 50 years of age, two or three fresh morning urine specimens should be evaluated by a cytology laboratory for the presence of tumor cells. The sensitivity of cytology in this setting is 30% when an upper tract tumor is present and 50% to 90% when a bladder tumor is present (with higher rates of detection for higher grades of cancer). However, because cystoscopy is the diagnostic procedure of choice when bladder cancer is suspected, many urologists suggest that cytology not be done until after cystoscopy has been performed, and then only when that procedure is negative for cancer but the clinician remains suspicious of the presence of a urinary tract neoplasia. A number of methods of detecting voided protein tumor markers (e.g., BTA, NMP22, Lewis x Antigen, CD44V) have been promoted for use in evaluating recurrence of bladder tumors (10). Although the use of voided tumor markers in the evaluation of patients with hematuria is promising, the available data are insufficient currently to warrant their routine use for that purpose.
Nevertheless, if neoplasia is a consideration (patient older than 40 to 50 years of age or younger but with a risk factor for bladder cancer), a urologist should be consulted and the patient should undergo cystoscopy. Risk factors for bladder cancer include heavy occupational exposure (e.g., to aromatic amines, dyes, benzidine, paint ingredients [see Chapter 8]); a history of smoking; pelvic irradiation; prior use of cyclophosphamide; gross, as opposed to microscopic, hematuria; a history of schistosomiasis; or prolonged daily use of analgesics (phenacetin, acetaminophen, and aspirin combinations have been reported to be associated with genitourinary cancer). If neoplasia is a strong consideration, the urologist might also suggest additional radiologic evaluation of the patient by sonography, CT scanning, magnetic resonance imaging, renal angiography, or retrograde pyelography.
If neoplasia is not strongly suspected and persistent hematuria is present or recurrent, the patient should be referred to a nephrologist for consideration of renal biopsy (see Chapter 48). There is no consensus regarding how long a patient with unexplained microscopic hematuria should be monitored. While in most patients microscopic hematuria is transient and/or benign, in others with persistent hematuria, genitourinary neoplasms or calculi are discovered 1 to 3 years after the onset of hematuria (18,19). It seems reasonable, therefore, to monitor patients with persistent hematuria (in particular older individuals and those with a history of cigarette smoking who are at increased risk of developing genitourinary tract carcinoma) with repeat urinalysis, urine cytology, CT scans, and cystoscopy for at least 3 to 4 years after discovery of hematuria.
Gross Hematuria
If gross hematuria is present, the evaluation should proceed initially in the same manner as for microscopic hematuria, but there are several caveats. Gross hematuria is more likely to reflect genitourinary tract cancer than is microscopic hematuria, and therefore warrants a definitive urologic evaluation regardless of age. In one large prospective study, patients with gross hematuria (even in patients younger than 40 years old), were two to four times more likely to have genitourinary tract cancer than those with microscopic hematuria (21). Patients with gross hematuria should always be referred to a urologist promptly, because the best time to identify the site of bleeding is when the bleeding is active. In patients with gross hematuria, plasma protein is lost into the urine and thereby can be detected by qualitative testing. However, the concentration of urinary protein rarely exceeds 1 g/day when it occurs as a result of blood in the urine alone.
The three-glass test is sometimes useful in determining the site of gross bleeding. This test is performed by having the patient void into containers in a sequence: The initial 10 mL of urine represents the urethral specimen, the middle portion of urine voided is nondiagnostic of a specific location, and blood in the terminal portion (the last few drops of urine) suggests that the site is likely to be the prostate, bladder neck, or proximal urethra. Blood present in all three specimens is not specific for the site of origin.
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The finding of blood in one of three specimens may correlate with clinical symptoms, but this relationship is not reliable.
The surveillance of a patient found to have gross hematuria depends on the cause. If no cause is found, close surveillance (every 6 months for several years) is indicated, because some of these patients have a serious underlying disorder, such as a tumor or glomerulonephritis. This surveillance should include reviewing the history, performing a physical examination, obtaining a urinalysis and determining the urea nitrogen and creatinine concentrations, and, in situations in which a tumor is considered, obtaining a urine specimen for cytologic examination and referring the patient to a urologist for a cystoscopic examination.
Hematospermia
The presence of blood in the ejaculate of men is an alarming but usually innocuous symptom. This problem occurs most often in men older than 40 years of age, and most often the episodes recur over several weeks or months. If hematospermia occurs in an otherwise asymptomatic man who has a normal physical examination (including rectal examination of the prostate and seminal vesicles) and a normal urinalysis, the patient should be reassured that it is innocuous and that no further workup is necessary. If there is any abnormality, further evaluation for benign prostatic hypertrophy or cancer of the prostate, seminal vesicles, bladder, or urethra should be considered and a urologist should be consulted.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.