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Asymptomatic Microscopic Hematuria in Adults: Summary of the AUA Best
Practice Policy Recommendations
GARY D. GROSSFELD, M.D.,
University of California, San Francisco, School of Medicine, San Francisco, California
J. STUART WOLF, JR., M.D.,
University of Michigan Medical School, Ann Arbor, Michigan
MARK S. LITWIN, M.D., M.P.H.,
University of California, Los Angeles, Schools of Medicine and Public Health, Los
Angeles, California
HEDVIG HRICAK, M.D., PH.D.,
Memorial Sloan-Kettering Cancer Center, New York, New York
CATHRYN L. SHULER, M.D.,
Kaiser Permanente, Portland, Oregon
DAVID C. AGERTER, M.D.,
Mayo Clinic, Rochester, Minnesota
PETER R. CARROLL, M.D.,
University of California, San Francisco, School of Medicine, San Francisco, California
The American Urological Association (AUA) convened the Best Practice Policy Panel
on Asymptomatic Microscopic Hematuria to formulate policy statements and
recommendations for the evaluation of asymptomatic microhematuria in adults. The
recommended definition of microscopic hematuria is three or more red blood cells
per high-power microscopic field in urinary sediment from two of three properly
collected urinalysis specimens. This definition accounts for some degree of hematuria
in normal patients, as well as the intermittent nature of hematuria in patients with
urologic malignancies. Asymptomatic microscopic hematuria has causes ranging from
minor findings that do not require treatment to highly significant, life-threatening
lesions. Therefore, the AUA recommends that an appropriate renal or urologic
evaluation be performed in all patients with asymptomatic microscopic hematuria
who are at risk for urologic disease or primary renal disease. At this time, there is no
consensus on when to test for microscopic hematuria in the primary care setting,
and screening is not addressed in this report. However, the AUA report suggests that
the patient's history and physical examination should help the physician decide
whether testing is appropriate. (Am Fam Physician 2001;63:1145-54.)
Blood in the urine (hematuria) can originate from any site along the urinary tract
and, whether gross or microscopic, may be a sign of serious underlying disease,
including malignancy. The literature agrees that gross hematuria warrants a
thorough diagnostic evaluation.1 By contrast, microscopic hematuria is an incidental
finding, and whether physicians should test for hematuria in asymptomatic patients
remains at issue. No major organization currently recommends screening for
microscopic hematuria in asymptomatic adults, even though bladder cancer is the
most commonly detected malignancy in such patients.2
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.
The American Urological Association (AUA) convened a Best Practice Policy Panel to
formulate recommendations for the evaluation of patients with asymptomatic
microhematuria. The panel does not offer recommendations regarding routine
screening for microscopic hematuria. The recommendations are based on extensive
review of the literature and the panel members' expert opinions. In addition to
urologists, the multispecialty panel included a family physician, a nephrologist and a
radiologist. Funding in support of panel activities was provided by the AUA. A
summary of the recommendations is presented in this article; the full text will be
published in Urology.3,4
The initial determination of microscopic hematuria should be based on microscopic
examination of urinary sediment from a freshly voided, clean-catch, midstream urine
specimen.
Hematuria can be measured quantitatively by any of the following: (1) determination
of the number of red blood cells per milliliter of urine excreted (chamber count), (2)
direct examination of the centrifuged urinary sediment (sediment count) or (3)
indirect examination of the urine by dipstick (the simplest way to detect microscopic
hematuria). Given the limited specificity of the dipstick method (65 percent to 99
percent for two to five red blood cells per high-power microscopic field), however,
the initial finding of microscopic hematuria by the dipstick method should be
confirmed by microscopic evaluation of urinary sediment.5-8
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).
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. To account for intermittent positive
tests for hematuria in patients with urologic malignancies,6,9 one group of
investigators10 proposed that patients with more than three red blood cells per highpower field from two of three properly collected urine specimens should be
considered to have microhematuria and, thus, should be evaluated appropriately.
However, before a decision is made to defer evaluation in patients with one or two
red blood cells per high-power field, risk factors for significant disease should be
taken into consideration (Table 1).4 High-risk patients should be considered for full
urologic evaluation after one properly performed urinalysis documenting the
presence of at least three red blood cells per high-power field.
The prevalence of asymptomatic microscopic hematuria varies from 0.19 percent to
as high as 21 percent.
In five population-based studies, the prevalence of asymptomatic microscopic
hematuria varied from 0.19 percent to 16.1 percent.7 Differences in the age and sex
of the populations screened, the amount of follow-up and the number of screening
studies per patient account for this range. In older men, who are at a higher risk for
significant urologic disease, the prevalence of asymptomatic microscopic hematuria
was as high as 21 percent.6,9,11-13
Patients with asymptomatic microscopic hematuria who are at risk for urologic
disease or primary renal disease should undergo an appropriate evaluation. In
patients at low risk for disease, some components of the evaluation may be deferred.
Asymptomatic microscopic hematuria has many causes, ranging from minor
incidental findings that do not require treatment to highly significant lesions that are
immediately life-threatening. Therefore, hematuria has been classified into four
categories: life-threatening; significant, requiring treatment; significant, requiring
observation; and insignificant1,10 (Table 2).1
Most studies in which patients with asymptomatic microscopic hematuria have
undergone full urologic evaluation (often including repeat urinalysis, urine culture,
upper urinary tract imaging, cystoscopy and urinary cytology) have included referralbased populations. A cause for asymptomatic microscopic hematuria was determined
in 32 percent to 100 percent of these patients.6,9-23
An algorithm for the initial evaluation of newly diagnosed asymptomatic microscopic
hematuria is provided in Figure 1.4 An approach to the urologic evaluation of
patients without conditions suggestive of primary renal disease is presented in Figure
2.4
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 or referral to a nephrologist.
TABLE 2
Reported Causes of Asymptomatic Microscopic
Hematuria
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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 followup 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, falsepositive 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 highpower 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
Cyclophosphamide (Cytoxan)
Hemorrhagic cystitis 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 contrastmaterial 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
Conditions affecting renal
parenchyma
IgA nephropathy (Berger's
disease)
Postinfectious
glomerulonephritis
Renal tumors (renal cell
carcinoma, angiomyolipoma,
oncocytoma)
Membranoproliferative
glomerulonephritis
Focal glomerular sclerosis
Rapidly progressing
glomerulonephritis
Vascular disorders (nutcracker
syndrome,15
malignant hypertension, sickle
cell trait or disease,
arteriovenous malformation, renal
vein thrombosis or infarct,
transplant rejection)
Secondary
Metabolic disorder (hypercalciuria,
glomerulonephritis
hyperuricuria)
Familial condition (polycystic
Lupus nephritis
Henoch-Schönlein syndrome kidney disease, medullary sponge
kidney)
Vasculitis (polyarteritis
Infection (acute or chronic
nodosa, Wegener's
pyelonephritis,
granulomatosis)
tuberculosis, cytomegalovirus
Essential mixed
infection, infectious
cryoglobulinemia
Hemolytic-uremic syndrome mononucleosis)
Papillary necrosis
Thrombotic
thrombocytopenic purpura
Medications (i.e., interstitial Extrarenal conditions
nephritis,
Tumors (renal pelvis, ureter,
analgesic nephropathy)
bladder, prostate)
Benign prostatic hyperplasia
Familial conditions
Stone or foreign body
Infections (cystitis, prostatitis,
Thin glomerular basement
urinary schistosomiasis,
membrane nephropathy
tuberculosis, condyloma
Hereditary nephritis
acuminatum)
(Alport's syndrome)
Systemic bleeding disorder or
Fabry's disease
coagulopathy
Trauma
Radiation therapy
Exercise12-14
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 followup 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.