The recommended definition of microscopic hematuria is three or more red blood cells per high-power field on microscopic evaluation of urinary sediment from two of three properly collected urinalysis specimens.

TABLE 1 Risk Factors for Significant Disease in Patients with Microscopic Hematuria

Smoking history Occupational exposure to chemicals or dyes (benzenes or aromatic amines) History of gross hematuria Age >40 years History of urologic disorder or disease History of irritative voiding symptoms History of urinary tract infection Analgesic abuse History of pelvic irradiation

Adapted with permission from Grossfeld GD, Wolf JS, Litwin MS, Hricak H, Shuler CL, Agerter DC, Carroll P. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy recommendations. Part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology 2001;57(4) (In press).

TABLE 2 Reported Causes of Asymptomatic Microscopic Hematuria

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

Significant proteinuria is defined as a total protein excretion of greater than 1,000 mg per 24 hours (1 g per day), or greater than 500 mg per 24 hours (0.5 g per day) if protein excretion is persistent or increasing or if other factors suggest the presence of renal parenchymal disease. In the absence of massive bleeding, a total protein excretion in excess of 1,000 mg per 24 hours would be unlikely and should prompt a thorough evaluation or nephrology referral24 (Figure 2).4
Red cell casts are virtually pathognomonic for glomerular bleeding. Unfortunately, they are a relatively insensitive marker. Therefore, it is useful to examine the character of the red blood cells.25 Dysmorphic urinary red blood cells show variation in size and shape and usually have an irregular or distorted outline. Such red blood cells are generally glomerular in origin. In contrast, normal doughnut-shaped red blood cells are generally due to lower urinary tract bleeding. Accurate determination of red blood cell morphology may require inverted phase contrast microscopy.
The percentage of dysmorphic red blood cells required to classify hematuria as glomerular in origin has not been adequately defined. In general, glomerular bleeding is associated with more than 80 percent dysmorphic red blood cells, and lower urinary tract bleeding is associated with more than 80 percent normal red blood cells.25,26 Percentages falling between these ranges are indeterminate and could represent bleeding from either source.
The initial evaluation of the urinary sediment generally identifies patients with parenchymal renal disease (Figure 1).4 Glomerular disease is most likely in this setting and may be associated with a variety of systemic diseases, including lupus erythematosus, vasculitis, malignancy and infections such as hepatitis and endocarditis. Glomerular diseases localized to the kidney include membranoproliferative glomerulonephritis, IgA nephropathy and crescentic glomerulonephritis. In addition, interstitial renal disease, such as drug-induced interstitial disease or analgesic nephropathy, may be associated with hematuria. If systemic causes are not identified, renal biopsy is usually recommended.
Patients with microscopic hematuria, a negative initial urologic evaluation and no evidence of glomerular bleeding are considered to have isolated hematuria. Although many such patients may have structural glomerular abnormalities, they appear to have low risk for progressive renal disease. Thus, the role of renal biopsy in this setting has not been defined. Nevertheless, because follow-up data are limited, these patients should be followed for the development of hypertension, renal insufficiency or proteinuria.
In patients without risk factors for primary renal disease, a complete urologic evaluation should be performed.
Complete urologic evaluation of microscopic hematuria includes a history and physical examination, laboratory analysis and radiologic imaging of the upper urinary tract followed by cystoscopic examination of the urinary bladder (Figure 2).4 In some instances, cytologic evaluation of exfoliated cells in the voided urine specimen may also be performed. If a careful history suggests a potential "benign" cause for microscopic hematuria (Figure 1),4 the patient should undergo repeat urinalysis 48 hours after cessation of the activity (i.e., menstruation, vigorous exercise, sexual activity or trauma).27 No additional evaluation is warranted if the hematuria has resolved. Patients with persistent hematuria require evaluation.

Initial Evaluation of Asymptomatic Microscopic Hematuria*

*--The recommended definition of microscopic hematuria is three or more red blood cells per high-power field on microscopic evaluation of two of three properly collected specimens. **--Proteinuria of 1+ or greater on dipstick urinalysis should prompt a 24-hour urine collection to quantitate the degree of proteinuria. A total protein excretion of >1,000 mg per 24 hours (1 g per day) should prompt a thorough evaluation or nephrology referral. Such an evaluation should also be considered for lower levels of proteinuria (>500 mg per 24 hours [0.5 g per day]), particularly if the protein excretion is increasing or persistent, or if there are other factors suggestive of renal parenchymal disease.

FIGURE 1. Initial evaluation of newly diagnosed asymptomatic microscopic hematuria. Adapted with permission from Grossfeld GD, Wolf JS, Litwin MS, Hricak H, Shuler CL, Agerter DC, Carroll P. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy recommendations. Part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology 2001;57(4) (In press).

In women, urethral and vaginal examinations should be performed to exclude local causes of microscopic hematuria. A catheterized urinary specimen is indicated if a clean-catch specimen cannot be reliably obtained (i.e., because of vaginal contamination or obesity). In uncircumcised men, the foreskin should be retracted to expose the glans penis, if possible. If a phimosis is present, a catheterized urinary specimen may be required.
The laboratory analysis begins with comprehensive examination of the urine and urinary sediment. The number of red blood cells per high-power field should be determined. In addition, the presence of dysmorphic red blood cells or red cell casts should be noted. The urine should also be tested for the presence and degree of proteinuria and for evidence of urinary tract infection. Patients with urinary tract infection should be treated appropriately, and urinalysis should be repeated six weeks after treatment.27 If the hematuria resolves with treatment, no additional evaluation is necessary. Serum creatinine should be measured. The remaining laboratory investigation should be guided by specific findings of the history, physical examination and urinalysis.

Urologic Evaluation of Asymptomatic Microscopic Hematuria

FIGURE 2. Urologic evaluation of asymptomatic microscopic hematuria. Adapted with permission from Grossfeld GD, Wolf JS, Litwin MS, Hricak H, Shuler CL, Agerter DC, Carroll P. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy recommendations. Part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology 2001;57(4) (In press).

Urothelial cancers, the target of a cytologic examination, are the most commonly detected malignancies in patients with microscopic hematuria.
Voided urinary cytology is recommended in all patients who have risk factors for transitional cell carcinoma (Table 1).4 This test can be a useful adjunct to cystoscopic evaluation of the bladder, especially in the determination of carcinoma in situ. In patients with asymptomatic microscopic hematuria who do not have risk factors for transitional cell carcinoma, urinary cytology or cystoscopy may be used. If cytology is chosen and malignant or atypical/suspicious cells are identified, cystoscopy is required because the presence of hematuria is a significant risk factor for malignancy in such patients.
Several recently identified voided urinary markers have been examined for the early detection of bladder cancer.1 At this time, insufficient data are available to recommend their routine use in the evaluation of patients with microscopic hematuria. Further studies are warranted to determine the role of these markers in the diagnostic evaluation of such patients.

The presence of significant proteinuria, red cell casts or renal insufficiency or a predominance of dysmorphic red blood cells in the urine should prompt an evaluation for renal parenchymal disease.

Intravenous urography, ultrasonography and computed tomography are used to evaluate the urinary tract in patients with microscopic hematuria. Because of lack of impact data, evidence-based imaging guidelines cannot be formulated.
In patients with microscopic hematuria, imaging can be used to detect renal cell carcinoma, transitional cell carcinoma in the pelvicaliceal system or ureter, urolithiasis and renal infection. Table 34 highlights imaging modalities used to evaluate the urinary tract.28-31 Intravenous urography (IVU) has traditionally been the modality of choice for imaging the urinary tract, and many still consider it to be the best initial study for the evaluation of microhematuria. However, IVU by itself has limited sensitivity in detecting small renal masses. When a mass is detected by IVU, further lesion characterization by ultrasonography, computed tomography (CT) or magnetic resonance imaging (MRI) is necessary because IVU cannot distinguish solid from cystic masses.
CT is the best imaging modality for the evaluation of urinary stones, renal and perirenal infections, and associated complications. For the detection of transitional cell carcinoma in the kidney or ureter, IVU is superior to ultrasonography. CT urography with abdominal compression results in reliable opacification of the collecting system, comparable to that obtained with IVU. High detection rates for transitional cell carcinoma on contrast-enhanced CT images have been reported, but the studies offer no statistical analysis.31,32 There are currently no studies comparing the performance of various diagnostic-imaging modalities in the detection of transitional cell carcinomas in the upper urinary tract. Retrograde pyelography is considered the best imaging approach for the detection and characterization of ureteral abnormalities, but this general opinion is not based on evidence.

TABLE 3 Imaging Modalities for Evaluation of the Urinary Tract

Modality	Advantages and disadvantages
Intravenous urography	Considered by many to be best initial study for evaluation of urinary tract Widely available and most cost-efficient in most centers Limited sensitivity in detecting small renal masses Cannot distinguish solid from cystic masses; therefore, further lesion characterization by ultrasonography, computed tomography or magnetic resonance imaging is necessary Better than ultrasonography for detection of transitional cell carcinoma in kidney or ureter
Ultrasonography	Excellent for detection and characterization of renal cysts Limitations in detection of small solid lesions (<3 cm)
Computed tomography	Preferred modality for detection and characterization of solid renal masses Detection rate for renal masses comparable to that of magnetic resonance imaging, but more widely available and less expensive

No data exist showing the impact of IVU, ultrasonography, CT or MRI on the management of patients with microscopic hematuria. Therefore, evidence-based imaging guidelines cannot be formulated. IVU currently remains the initial evaluation of choice for upper tract imaging in patients with microhematuria for several reasons: (1) the technology is standardized, (2) previous series examining patients with microhematuria have been based on this modality, (3) the rate of missed diagnoses is low when IVU is followed by appropriate studies and (4) IVU is less expensive than CT in most centers. However, the advantage of CT over IVU is that CT has the highest efficacy for the range of possible underlying pathologies, and it shortens the duration of the diagnostic work-up.
If CT is chosen as the initial upper tract study, the imaging protocol should be adapted to the diagnostic goals, such as the exclusion of urolithiasis and renal neoplasm. CT urography spiral (helical) is preferred if the technology is available. Neither oral nor rectal contrast medium is required. The CT protocol should start with a noncontrast scan. If this scan demonstrates urolithiasis in a patient who is at low risk for underlying malignancy (Table 1),4 no further scanning is needed. In all other patients, including those in whom a urinary calculus is not detected, intravenous contrast medium should be injected. CT scout (topogram) or plain-film abdominal radiography (depending on the equipment available) can be performed at the end of the CT examination to assess the ureters and bladder in an IVUlike fashion.
Cystoscopic evaluation of the bladder (complete visualization of the bladder mucosa, urethra and ureteral orifices) is necessary to exclude the presence of bladder cancer.
Cystoscopy as a component of the initial office evaluation of microscopic hematuria is recommended in all adult patients more than 40 years of age and in patients less than 40 years of age with risk factors for bladder cancer. This includes patients in whom upper tract imaging reveals a potentially benign source for bleeding. Cystoscopy appears to have a low yield in select patients at low risk for bladder cancer, including men and women younger than 40 years with no risk factors for this malignancy.10,14,20,21,33 In these patients, initial cystoscopy may be deferred, but urinary cytology should be performed.
Initial diagnostic cystoscopy can be performed under local anesthesia using a rigid or flexible cystoscope. Compared with rigid cystoscopy, flexible cystoscopy causes less pain and is associated with fewer post-procedure symptoms.34-36 In addition, positioning and preparation of the patient are simplified, and procedure time is reduced.34 Flexible cystoscopy appears to be at least equivalent in diagnostic accuracy to rigid cystoscopy; for some lesions (i.e., those at the anterior bladder neck), it may be superior.34,37
Because some patients with a negative initial evaluation for asymptomatic microhematuria eventually develop significant urologic disease, some form of follow-up is indicated.
Although most patients with a negative initial evaluation for asymptomatic microhematuria do not develop significant urologic disease, some patients do. Consequently, some form of follow-up is indicated. Because the appearance of hematuria can precede the diagnosis of bladder cancer by many years,38 such follow-up seems especially important in high-risk groups, including patients older than 40 years and those who use tobacco or whose occupational exposures put them at risk.15 Because the risk of life-threatening lesions in patients with a negative initial evaluation is low and the data regarding follow-up in such patients are sparse, recommendations regarding appropriate follow-up must be based on consensus opinion, in addition to review of the available literature-based evidence.

Computed tomography is the best imaging modality for the evaluation of urinary stones, renal and perirenal infections, and associated complications.

In patients with a negative initial evaluation of asymptomatic microscopic hematuria, consideration should be given to repeating urinalysis, voided urine cytology and blood pressure determination at six, 12, 24 and 36 months. Although cytology may not be a sensitive marker for detecting low-grade transitional cell carcinoma, it detects most high-grade tumors and carcinomas in situ, particularly if the test is repeated. Such high-grade lesions are the most likely to benefit from early detection.
Additional evaluation, including repeat imaging and cystoscopy, may be warranted in patients with persistent hematuria in whom there is a high index of suspicion for significant underlying disease. In this setting, the clinical judgment of the treating physician should guide further evaluation. Immediate urologic reevaluation, with consideration of cystoscopy, cytology or repeat imaging, should be performed if any of the following occur: (1) gross hematuria, (2) abnormal urinary cytology or (3) irritative voiding symptoms in the absence of infection. If none of these occurs within three years, the patient does not require further urologic monitoring. Further evaluation for renal parenchymal disease or referral to a nephrologist should be considered if hematuria persists and hypertension, proteinuria or evidence of glomerular bleeding (red cell casts, dysmorphic red blood cells) develops.
The AUA panel members thank Lisa Cowen, Ph.D., and Carol Schwartz, M.P.H., R.D., for assistance with the manuscript.

The Authors

GARY D. GROSSFELD, M.D.,
is assistant professor of urology at the University of California, San Francisco, School of Medicine.
J. STUART WOLF, JR., M.D.,
is associate professor of surgery (urology) at the University of Michigan Medical School, Ann Arbor.
MARK S. LITWIN, M.D., M.P.H.,
is associate professor of urology and health services at the University of California, Los Angeles, Schools of Medicine and Public Health.
HEDVIG HRICAK, M.D., PH.D.,
is chair of the radiology department at Memorial Sloan-Kettering Cancer Center, New York City.
CATHRYN L. SHULER, M.D.,
is a physician with Kaiser Permanente, Portland, Ore.
DAVID C. AGERTER, M.D.,
is chair of the family medicine department at Mayo Clinic, Rochester, Minn.
PETER R. CARROLL, M.D.,
is professor and chair of the urology department at the University of California, San Francisco, School of Medicine.

Evaluation of Asymptomatic Microscopic Hematuria in Adults

TIMOTHY R. THALLER, M.D
University of Kansas Medical Center, Kansas City, Kansas
LESTER P. WANG, M.D.
Valley Urology Center, Renton, Washington

In patients without significant urologic symptoms, microscopic hematuria is occasionally detected on routine urinalysis. At present, routine screening of all adults for microscopic hematuria with dipstick testing is not recommended because of the intermittent occurrence of this finding and the low incidence of significant associated urologic disease. However, once asymptomatic microscopic hematuria is discovered, its cause should be investigated with a thorough medical history (including a review of current medications) and a focused physical examination. Laboratory and imaging studies, such as intravenous pyelography, renal ultrasonography or retrograde pyelography, may be required to determine the degree and location of the associated disease process. Cystourethroscopy is performed to complete the evaluation of the lower urinary tract. Microscopic hematuria associated with anticoagulation therapy is frequently precipitated by significant urologic pathology and therefore requires prompt evaluation. (Am Fam Physician 1999;60:1143-54.)

Microscopic hematuria is defined as the excretion of more than three red blood cells per high-power field in a centrifuged urine specimen.1 Because the degree of hematuria bears no relation to the seriousness of the underlying cause, hematuria should be considered a symptom of serious disease until proved otherwise.

Microscopic hematuria is defined as the excretion of more than three erythrocytes per high-power field, but the degree of hematuria does not correlate with the seriousness of the underlying cause of the bleeding.

The widespread use of dipstick urinalysis in clinical practice and health screening has resulted in increased recognition of microscopic hematuria and has raised concerns about the appropriate diagnostic investigation. The prevalence of asymptomatic microscopic hematuria in adult men and postmenopausal women has been reported to range from 10 percent to as high as 20 percent.2-4 Routine screening of all adults for microscopic hematuria with dipstick testing is not currently recommended because of the intermittent occurrence of this finding and the low incidence of significant associated urologic disease.

Detection of Hematuria

In dipstick urinalysis for microscopic hematuria, false-positive results may occur because of dehydration, myoglobinuria or contamination with menstrual fluid or oxidizing agents. False-negative results may be due to reducing agents, low urinary pH or air-exposed dipsticks.

Dipstick Tests for Hematuria
In clinical practice, dipstick urinalysis is the test most commonly used to detect urinary tract disorders in asymptomatic patients. In this test, cellulose strips dipped into a urine specimen record the ability of hemoglobin to catalyze the reaction between hydrogen peroxide and a chromogen. The resulting reaction causes the chromogen to turn green, with the degree of color change directly related to the amount of hemoglobin present in the urine specimen. A spotted pattern to the dipstick indicates the presence of free hemoglobin.5,6
Dipstick testing has been shown to be 91 to 100 percent sensitive and 65 to 99 percent specific for the detection of hemoglobin. False-positive test results have been reported in the presence of myoglobinuria and oxidizing 7contaminants (e.g., hypochlorite, povidone and bacterial peroxidases), contamination of the urine specimen with menstrual blood, and dehydration with elevation of urine specific gravity.1,5 False-negative results have been reported in the presence of reducing agents (e.g., ascorbic acid), a urinary pH of less than 5.1 and dipsticks that have been exposed to air.1,5

FIGURE 1. Typical morphology of erythrocytes from a urine specimen revealing microscopic hematuria. (phase contrast microscopy, 3100)

FIGURE 2. Dysmorphic erythrocytes from a urine specimen. These cells suggest a glomerular cause of microscopic hematuria. (phase contrast microscopy, 3 100)

Urine Specimen Collection and Preparations
Several factors can influence the microscopic detection of erythrocytes in urine. Procurement of a urine sample using a catheter may cause urethral trauma that results in variable degrees of hematuria. A clean-catch midstream urine specimen should be obtained using aseptic technique to avoid contamination from the external genitalia. The first urine in the morning is typically the best specimen because erythrocytes are heat preserved in acidic and concentrated urine.
A prolonged delay from specimen collection to analysis can result in a false test interpretation. When a urine specimen cannot be examined within one hour of collection, it should be refrigerated to prevent overgrowth of bacteria, changes in urinary pH and disintegration of red and white cell casts. These conditions may occur if the specimen remains at room temperature for a long period.
Standardization of the analysis procedure is also essential to achieve an accurate result. Centrifugation is typically performed on a fixed volume of urine (5 mL) for five minutes at 3,000 rotations per minute, after which the supernatant is poured off and the remaining sediment is resuspended in the centrifuge tube by gently tapping the bottom of the tube. A pipette is used to sample the residual fluid and transfer it to a glass slide; a coverslip is applied to the slide for the microscopic evaluation.5 The specimen is examined under high magnification (3 400) to determine cell type and distinct morphologic features. Results are recorded as the number of red blood cells per high-power field.

Findings on Microscopy
On phase contrast microscopy, erythrocytes may display morphologic features that are helpful in differentiating glomerular and nonglomerular causes of microscopic hematuria8 (Figures 1 and 2).
Dysmorphic erythrocytes are characterized by an irregular outer cell membrane and suggest hematuria of glomerular origin. Red blood cell casts are also associated with a glomerular cause of hematuria. Acanthocytes, which are ring-formed erythrocytes with one or more membrane protrusions of variable size and shape, may represent an early form of dysmorphic erythrocytes and are a marker for hematuria of glomerular origin.
Erythrocytes of uniform character are classified as isomorphic and suggest hematuria of lower urinary tract origin. Microscopic clots of clumped erythrocytes in urine are also suggestive of lower urinary tract bleeding.
The presence of both dysmorphic and isomorphic erythrocytes in urine represents a mixed morphologic pattern of nonspecific origin.

Diagnosis of Hematuria

TABLE 1 Substances and Medications Affecting Urine Color

Artificial food coloring Beets Berries Chloroquine (Aralen) Furazolidone (Furoxone) Hydroxychloroquine (Plaquenil) Nitrofurantoin (Furadantin) Phenazopyridine (Pyridium) Phenolphthalein Rifampin (Rifadin)

Information from Restrepo NC, Carey PO. Evaluating hematuria in adults. Am Fam Physician 1989; 40(2):149-56, and Drugdex system. Englewood: Colo.: Micromedex, Inc., 1999. Accessed Sept. 24, 1998.

History and Physical Examination
The initial step in the evaluation of microscopic hematuria is a thorough medical history, including a review of prescription and nonprescription medications, a history of ingestion of certain foods and an inquiry for specific conditions (Tables 1 and 2).9,10
The information obtained in the medical history is used to screen for the multiple potential causes of both glomerular and nonglomerular conditions that can lead to microscopic hematuria (Table 3).11-15 IgA nephropathy (Berger's disease) is the most common cause of glomerular hematuria. Drug-induced glomerular causes of hematuria include nonsteroidal anti-inflammatory drugs and certain antibiotics associated with analgesic nephropathy and interstitial nephritis (Table 2).9,10
One common nonglomerular medical cause of hematuria is papillary necrosis. This condition should be considered in patients with diabetes mellitus, black patients with sickle cell trait or disease, and patients known to be analgesic abusers. Other common nonglomerular causes of hematuria include urothelial tumors, urolithiasis, benign prostatic hyperplasia (BPH) and urinary tract infection.
The physical examination should take into account the multiple potential causes of hematuria and include the following points: evaluation of the cardiovascular system for irregular cardiac rhythm, heart murmur or hypertension; evaluation of the abdomen for organomegaly or flank mass; evaluation of the prostate and external genitalia; and evaluation of the extremities for peripheral edema, petechiae or mottling (Table 4).
Urothelial cancers should also be considered in the evaluation of microscopic hematuria. Risk factors for these malignancies, particularly transitional cell carcinoma, are listed in Table 5.16

Laboratory Tests
The initial laboratory studies are determined by pertinent information obtained from the medical history and physical examination. Formal urinalysis is performed to document the degree of hematuria, determine the morphologic features of erythrocytes and evaluate urinary crystals and casts. If pyuria or bacteriuria is present, a urine culture with sensitivity testing should be obtained to rule out infectious urinary tract pathogens. Screening laboratory tests typically consist of coagulation studies, a complete blood count, serum chemistries and serologic studies for glomerular causes of hematuria as directed by the medical history.
Further urologic evaluation is warranted if more than three red blood cells per high-power field are found on at least two of three properly collected urine specimens or if high-grade microscopic hematuria (more than 100 red blood cells per high-power field) is found on a single urinalysis.17 The only exceptions are children with persistent microscopic hematuria without proteinuria, in whom the most likely diagnoses include thin glomerular basement membrane nephropathy, idiopathic hypercalciuria, IgA nephropathy and Alport's syndrome.

TABLE 2 Mechanisms by Which Selected Drugs May Cause Hematuria

Mechanism	Drugs
Interstitial nephritis	Captopril (Capoten) Cephalosporins Chlorothiazide (Diuril) Ciprofloxacin (Cipro) Furosemide (Lasix) NSAIDs Olsalazine (Dipentum) Omeprazole (Prilosec) Penicillins Rifampin (Rifadin) Silver sulfadiazine (Silvadene) Trimethoprim-sulfamethoxazole (Bactrim, Septra)
Papillary necrosis	Acetylsalicylic acid (aspirin) NSAIDs
Hemorrhagic cystitis	Cyclophosphamide (Cytoxan) Ifosfamide (Ifex) Mitotane (Lysodren)
Urolithiasis	Carbonic anhydrase inhibitors Dichlorphenamide (Daranide) Indinavir (Crixivan) Mirtazapine (Remeron) Ritonavir (Norvir) Triamterene (Dyrenium)

NSAIDs = nonsteroidal anti-inflammatory drugs. Information from Restrepo NC, Carey PO. Evaluating hematuria in adults. Am Fam Physician 1989; 40(2):149-56, and Drugdex system. Englewood: Colo.: Micromedex, Inc., 1999. Accessed Sept. 24, 1998.

Radiographic Investigation
The initial radiographic study is intravenous pyelography (IVP), or excretory urography. The purpose of the study is to obtain an anatomic and functional evaluation of the upper and lower urinary tract. Before IVP is performed, the collected urine specimen should undergo microscopic examination to exclude an infectious cause of hematuria. Some centers use renal ultrasonography as an initial test to avoid exposing patients to intravenous contrast media; however, subtle findings in the renal collecting system may be difficult to detect by ultrasonography alone.
Risk factors for contrast uropathy have been described (Table 6).18 Because preexisting renal insufficiency is the most important risk factor for renal failure, the serum creatinine concentration should always be measured before any contrast examination is performed. Early studies reported a 4.7 percent overall incidence of adverse reactions to conventional ionic high-osmolar contrast media.19 Although most of these reactions were considered minor, true anaphylactic reactions have been described. The incidence of death after the intravenous administration of conventional contrast media has been reported to be one case per 40,000 contrast-material injections.19 Newer, nonionic low-osmolar contrast media are associated with fewer adverse effects than traditional, less expensive, ionic high-osmolar agents.20
Metformin (Glucophage) is an oral antihyperglycemic agent commonly used in the management of type 2 diabetes (formerly termed noninsulin-dependent diabetes). This drug is eliminated primarily by the kidneys. Because of potential exacerbation of acute renal failure and lactic acidosis, metformin should be discontinued at the time of radiologic studies involving intravascular administration of iodinated contrast materials and for 48 hours subsequent to the prodecure. Current recommendations include withholding metformin for at least 48 hours before and after the radiographic procedure. The drug should only be restarted after renal function has been reevaluated and found to be normal.21
With excretory urography, tomography is typically performed to increase recognition of renal masses, fine renal calcifications and paranephric structures. Oblique images are obtained to assist in evaluation of ureteral lesions, differentiation of extrinsic and intrinsic renal or ureteral masses and visualization of the posterolateral aspect of the bladder. Delayed images are helpful in cases of obstruction in which the nephrogram phase is seen on IVP but the collecting system is not yet visualized.18
If the use of intravenous contrast material is contraindicated or if incomplete visualization of the lower urinary tract occurs, retrograde pyelography should be performed. Typically, the combination of retrograde pyelography and ultrasonography is employed to increase sensitivity in the detection of solid renal masses. However, renal ultrasonography cannot detect the subtle mucosal abnormalities that occur with transitional cell carcinoma or small, echogenic ureteral calculi. Compared with renal ultrasonography, computed tomography (CT) is more sensitive in detecting renal masses and subtle filling defects of the renal collecting system.22 Recently, unenhanced helical CT scans have provided accurate evaluation of patients with acute flank pain through the precise determination of calculus size and location.23 Despite advancements in radiographic imaging, the role of CT or ultrasonography as the primary imaging modality in the work-up of microscopic hematuria has not been established.

Lower Urinary Tract Investigation
Whereas radiographic imaging allows evaluation of the upper urinary tract, cystourethroscopy provides definitive evaluation of the lower urinary tract. In addition to direct visualization of the urethra, prostate and bladder, washings and biopsies of suspicious bladder lesions can be performed during cystourethroscopy.
Cytology obtained from washings is useful in detecting poorly differentiated sessile and in situ bladder lesions. With in situ bladder cancer, the results of cytologic analysis are often positive before lesions are seen with cystoscopy.1

TABLE 3 Glomerular and Nonglomerular Causes of Hematuria

Glomerular causes

Nonglomerular causes

Primary glomerulonephritis IgA nephropathy (Berger's disease) Postinfectious glomerulonephritis Membranoproliferative glomerulonephritis Focal glomerular sclerosis Rapidly progressing glomerulonephritis Secondary glomerulonephritis Lupus nephritis Henoch-Schönlein syndrome Vasculitis (polyarteritis nodosa, Wegener's granulomatosis) Essential mixed cryoglobulinemia Hemolytic-uremic syndrome Thrombotic thrombocytopenic purpura Medications (i.e., interstitial nephritis, analgesic nephropathy) Familial conditions Thin glomerular basement membrane nephropathy Hereditary nephritis (Alport's syndrome) Fabry's disease Exercise12-14

Conditions affecting renal parenchyma Renal tumors (renal cell carcinoma, angiomyolipoma, oncocytoma) Vascular disorders (nutcracker syndrome,15 malignant hypertension, sickle cell trait or disease, arteriovenous malformation, renal vein thrombosis or infarct, transplant rejection) Metabolic disorder (hypercalciuria, hyperuricuria) Familial condition (polycystic kidney disease, medullary sponge kidney) Infection (acute or chronic pyelonephritis, tuberculosis, cytomegalovirus infection, infectious mononucleosis) Papillary necrosis Extrarenal conditions Tumors (renal pelvis, ureter, bladder, prostate) Benign prostatic hyperplasia Stone or foreign body Infections (cystitis, prostatitis, urinary schistosomiasis, tuberculosis, condyloma acuminatum) Systemic bleeding disorder or coagulopathy Trauma Radiation therapy Indwelling catheters Drugs (heparin, warfarin [Coumadin], cyclophosphamide [Cytoxan])

Adapted with permission from Ahmed Z, Lee J. Asymptomatic urinary abnormalities. Hematuria and proteinuria. Med Clin North Am 1997;81:641-52; additional information from references 12 through 15.

Other Investigations
When no cause for microscopic hematuria is found with cystourethroscopy and appropriate radiographic imaging, further studies may be considered. These studies include CT scanning, renal angiography and flexible ureterorenoscopy. No consensus has been reached on the indications for renal biopsy in patients with hematuria, but this procedure may be indicated to rule out glomerular causes of hematuria.1 Despite a complete and exhaustive work-up, no specific cause is identified in approximately 20 percent of patients with microscopic hematuria.24

Concurrent metformin (Clucophage) ingestion may precipitate lactic acidosis and cute renal failure in patientsundergoing intravenous pyelography with iodinated contrast media.

Molecular markers recently introduced into clinical practice to assist with the follow-up evaluation of urothelial carcinomas have yet to be labeled for the evaluation of hematuria. The two assays currently labeled for clinical use by the U.S. Food and Drug Administration are the bladder tumor antigen (BTA) test and the nuclear matrix protein (NMP-22) test.17,25 The BTA test is a latex agglutination assay for the qualitative detection of a basement membrane antigen in a voided urine specimen. The NMP-22 test involves the quantitative detection of a specific nuclear matrix protein in a voided urine specimen. Although these assays offer great potential for the early detection of recurrent bladder carcinoma, their role in the evaluation of hematuria is still uncertain.
A standard reference algorithm for the evaluation and treatment of asymptomatic microscopic hematuria is presented in Figure 3. This systematic approach can be useful in identifying and managing causes of hematuria ranging from infection to BPH26 to cancer.

TABLE 4 Physical Examination Findings and Associated Causes of Hematuria

Physical examination finding	Cause of hematuria
General (systemic) examination
Severe dehydration	Renal vein thrombosis
Peripheral edema	Nephrotic syndrome, vasculitis
Cardiovascular system
Myocardial infarction	Renal artery embolus or thrombus
Atrial fibrillation	Renal artery embolus or thrombus
Hypertension	Glomerulosclerosis with or without proteinuria
Abdomen
Bruit	Arteriovenous fistula
Genitourinary system
Enlarged prostate	Urinary tract infection
Phimosis	Urinary tract infection
Meatal stenosis	Urinary tract infection

 

TABLE 5 Risk Factors for Urothelial Carcinoma

Cigarette smoking Occupational exposures Aniline dyes Aromatic amines Benzidine Dietary nitrites and nitrates Analgesic abuse (e.g., phenacetin) Chronic cystitis and bacterial infection associated with urinary calculi and obstruction of the upper urinary tract Urinary schistosomiasis Cyclophosphamide (Cytoxan) Pelvic irradiation

Information from Messing EM, Catalona W. Urothelial tumors of the urinary tract. In: Walsh PC, ed. Campbell's Urology. 7th ed. Philadelphia: Saunders, 1998:2327-410.

Special Considerations

TABLE 6 Risk Factors for Contrast Uropathy

Dehydration Diabetes with azotemia Cardiac decompensation History of allergy Asthma Hay fever Seafood allergy Others, including allergic reactions to antibiotics Previous reaction to contrast media Renal insufficiency

Information from Friedenberg RM. Excretory urography in the adult. In: Walsh PC, ed. Campbell's Urology. 6th ed. Philadelphia: Saunders, 1992:412-34.

Hematuria During Anticoagulation
Microscopic hematuria is commonly encountered in patients taking anticoagulant drugs. Although it may be easy to attribute this hematuria solely to anticoagulation therapy, significant urologic causes have been reported in 13 to 45 percent of such patients.27,28 Current recommended anticoagulation schedules do not predispose patients to hematuria.27 The most common causes of anticoagulant-associated hematuria include BPH, inflammatory conditions, urolithiasis, papillary necrosis and cancers of the upper and lower urinary tract.
Hematuria Following Exercise
Asymptomatic microscopic hematuria resulting from strenuous exercise has been well documented in association with a variety of contact and noncontact sports activities.12-14 The degree of hematuria is believed to be related to the intensity and duration of exercise.12 Although exercise-induced hematuria is typically a benign, self-limited process, coexisting urinary tract pathology may exist and must be carefully excluded.
Exercise-induced microscopic hematuria almost always resolves within 72 hours of onset in patients who do not have underlying urinary tract abnormality. However, if the hematuria is present on repeat urinalysis after 72 hours of rest, further urologic evaluation may be indicated.

Final Comment
Asymptomatic microscopic hematuria is commonly nephric in origin, whereas gross hematuria is often uroepithelial in origin. Gross, painless hematuria is often the first manifestation of a urothelial tumor. However, the degree of hematuria bears no relation to the seriousness of the underlying disease. Consequently, the microscopic finding of blood in the urine should be considered a serious symptom until significant pathology has been excluded.
Phase contrast microscopy is currently the best initial method of documenting microscopic hematuria. The evaluation often includes intravenous pyelography, cystourethroscopy and urinary cytology.
Unfortunately, consensus is lacking regarding the management of persistent asymptomatic microscopic hematuria of unknown etiology. Recommended surveillance schedules for patients with a previous negative evaluation for unexplained microscopic hematuria include urinalysis and voided urinary cytology annually until the hematuria resolves, or for up to three years if microscopic hematuria persists. Any significant increase in the degree of microscopic hematuria (more than 50 red blood cells per high-power field), an episode of gross hematuria or the new onset of irritative voiding symptoms in the absence of infection warrants a complete reevaluation.17
Additional large population-based studies of the prevalence of asymptomatic microscopic hematuria and its relationship with age and sex are needed before definitive recommendations can be formalized to practice guidelines.

Hematuria

FIGURE 3. Algorithm for the evaluation and treatment of hematuria. (RBC = red blood cell; WBC = white blood cell; BUN = blood urea nitrogen; CBC = complete blood count; PT = prothrombin time; PTT = partial thromboplastin time; IVP = intravenous pyelography; KUB = plain radiograph of kidney, ureter and bladder; CT = computed tomography; TURP = transurethral resection of the prostate)

The Authors

TIMOTHY R. THALLER, M.D.
is currently in private practice at Statesboro Urologic Clinic, P.C., Statesboro, Ga. He received his medical degree from Louisiana State University School of Medicine in Shreveport and completed a residency in urology at the University of Kansas Medical Center, Kansas City, Kan., where he served as chief resident.
LESTER P. WANG, M.D.
is in private practice at Valley Urology Center, Renton, Wash. Dr. Wang completed a residency in urology at the University of Minnesota, Minneapolis, and a fellowship in endourology at Baylor College of Medicine, Houston.