1. health and fitness
2. disease

Urology Didactics
5-25-04
„ Chris
Vincent – Hematuria
„ Rebecca Sellers – Kidney Stones
„ SFM – Online – Prostate CA
(Microscopic Asymptomatic)
Hematuria
Chris Vincent
Tuesday, May 25, 2004
Illustrative Case (NEJM)
„
An otherwise healthy 48-year-old woman is
found to have microscopic hematuria (5 red
cells per high-power field) on a urinalysis
performed by a life insurance company. No
other laboratory abnormalities are identified;
the serum creatinine concentration is 0.8
mg/dL. The woman reports no symptoms and
is a nonsmoker. Her blood pressure is
118/74, and findings on physical exam are
normal. How should she be evaluated?
Cohen RA, Brown RS. Microscopic hematuria. N Engl J Med June 5, 2003;348:2330-8
Hematuria Outline
„ Definition
„ Prevalence
„ Causes
„ Workup
„ Follow
up
Hematuria Outline
„ Definition
„ Prevalence
„ Causes
„ Workup
„ Follow
up
Hematuria Definition
„ Urine
dipstick detects 1-2/HPF so very
sensitive but not specific (myoglobinuria &
hemoglobinuria cause + results)
„ Microscopy essential if dipstick +
„ “Normal” varies by author: 1-10/HPF
„ Most accept 0-3/HPF as nml, >3 abnml
Hematuria Definition
„ “Red”
urine not always due to blood
„ Drugs, Prophyria, foods cause red urine
Substances Affecting Urine Color
„
„
„
„
„
„
„
„
„
„
Artificial food coloring
Beets
Berries
Chloroquine (Aralen)
Furazolidone (Furoxone)
Hydroxychloroquine (Plaquenil)
Nitrofurantoin (Furadantin)
Phenazopyridine (Pyridium)
Phenolphthalein
Rifampin (Rifadin)
Hematuria Definition
Hematuria Outline
„ Definition
„ Prevalence
„ Causes
„ Workup
„ Follow
up
Hematuria Prevalence
„ Varies
by study/population group/age
„ 0.2% to 20% cited
„ Usually accepted: 2%
Hematuria Outline
„ Definition
„ Prevalence
„ Causes
„ Workup
„ Follow
up
Hematuria Causes
„ By
Age
– <40-50 vs. >40-50
„ By
Origin
– Glomerular vs. Non-glomerular
„ By
Duration
– Transient vs. Persistent
(Some) Hematuria Causes by Age
All
<40-50
> 40-50
Stones
Thin Basement
Membrane
Transitional cell
CA
Infection
Trauma
Renal Cell CA
IgA Nephropathy Medullary sponge
Mild Focal GN
Polycystic kidney
Bladder CA
Exercise
Hematuria Causes by Origin
Hematuria Causes by Age & Origin
Hematuria Causes by Age & Origin
Hematuria Causes by Age & Origin
Hematuria Causes by Age & Duration
Hematuria Outline
„ Definition
„ Prevalence
„ Causes
„ Workup
„ Follow
up
Hematuria Workup
„ Recommendations
& guidelines vary
„ Depends on age, gender & “risk
factors”
„ Availability of tests
„ Availability/opinion of referral
specialists
Hematuria Workup
„ Basic
workup before referral
– H&P!
– Lab
– Imaging
„ Referral
– Nephrology
– Urology
Hematuria Workup
„ Basic
workup before referral
– H&P!
– Lab
– Imaging
„ Referral
– Nephrology
– Urology
Hematuria Workup – H&P
„ Dysuria,
fever?
– UTI, pylo, urethritis
„ Recent
URI?
– PSGN, IgA nephropathy
„ Unilateral
pain
– Stones, clot
„ BPH
Sx (men)
„ Menstrual Hx (women)
„ Medications (see next slide)
– Warfarin: not a cause per se, but indicates
possible underlying condition
Hematuria Workup – H&P
Mechanism
Drugs
Interstitial
nephritis
Captopril (Capoten),
Capoten), Cephalosporins,
Cephalosporins, Chlorothiazide
),
Ciprofloxacin
(Cipro
), Furosemide (Lasix),
(Diuril),
Lasix),
Diuril
(Cipro),
NSAIDs,
NSAIDs, Olsalazine (Dipentum),
Dipentum), Omeprazole
(Prilosec),
Prilosec), Penicillins,
Penicillins, Rifampin (Rifadin),
Rifadin), Silver
sulfadiazine (Silvadene
), Trimethoprim(Silvadene),
Trimethoprimsulfamethoxazole (Bactrim,
Bactrim, Septra)
Septra)
Papillary necrosis
Acetylsalicylic acid (aspirin), NSAIDs
Hemorrhagic
cystitis
Cyclophosphamide (Cytoxan),
Cytoxan), Ifosfamide (Ifex),
Ifex),
Mitotane (Lysodren)
)
Lysodren
Urolithiasis
Carbonic anhydrase inhibitors, Dichlorphenamide
(Daranide),
Daranide), Indinavir (Crixivan),
Crixivan), Mirtazapine
(Remeron),
Remeron), Ritonavir (Norvir),
Norvir), Triamterene
(Dyrenium)
Dyrenium)
Hematuria Workup – H&P
„ Fam
Hx
– Sickle cell, hereditary nephritis, polycystic
kidney
„ “Risk
Factors” for CA
– Age > 40-50, cigarette smoking, occupational
exposure to certain chemicals (leather, dye,
and rubber or tire manufacturing), heavy
phenacetin use, past Rx w/ high doses of
cyclophosphamide, ingestion of aristolochic
acid (found in some herbal weight-loss
preparations), and schistosomiasis
Hematuria Workup – H&P
„ PE
– V.S.
– BP!!! Temp
„ Pallor?
(anemia)
„ Back (CVAT)
„ Abd Mass?
„ Pelvic/rectal (examine urethra,
prostate/uterus)
Hematuria Workup
„ Basic
workup before referral
– H&P!
– Lab
– Imaging
„ Referral
– Nephrology
– Urology
Hematuria Workup - Lab
„ UA!
„ CBC
„ Chemistries
„ Other
Urine tests
– 24 hour
– cytology
„ UA
Hematuria Workup - Lab
– Gross visual inspection
– Dipstick for amount of blood, protein, nitrites,
leukocytes
– Micro - look for casts & abnormal cells
ƒ RBC Casts – glomerular origin
ƒ Crenated RBC’s – concentrated urine – no
significance
ƒ Acanthocytes – 98% - 100% specific for
glomerular origin but only 52% to 73%
sensitive
– RBC’s may have hemolyzed if urine dilute
Hematuria Workup - Lab
Hematuria Workup - Lab
Hematuria Workup - Lab
RBC Casts
Hematuria Workup - Lab
Crenated RBC’s
Hematuria Workup - Lab
Acanthocytes
Hematuria Workup - Lab
„ CBC
– Look for anemia, abnormal red cell
morphology, leukocytosis
„ Chemistries
– BUN, Creatinine
„ Other
Urine tests
– 24 hour for protein
– Cytology – 3 serial AM voids
– Sens = 72 + 6%, Spec = 98 + 2 %
Hematuria Workup
„ Basic
workup before referral
– H&P!
– Lab
– Imaging
„ Referral
– Nephrology
– Urology
Hematuria Workup - Imaging
„ IVP
– Old “Gold Standard”
– Good visualization of collecting system & ureters
– May miss bladder lesions, expensive, dye Rxn
„ US
– Safer than IVP, good visualization of kidneys
– May miss small (<3 cm) lesions
„ CT
– Most sensitive and specific, new “Gold Standard”
– Expensive, dye Rxn
Hematuria Workup – Imaging
Risk Factors for Contrast Urography
„ Dehydration,
renal insufficiency, cardiac
decompensation
„ Diabetes with azotemia
„ History of dye allergy or previous reaction
to contrast media
„ Asthma, hay fever
„ Seafood allergy?
„ Other allergies, including allergic reactions
to antibiotics
Hematuria Workup
Hematuria Workup
„ Basic
workup before referral
– H&P!
– Lab
– Imaging
„ Referral
– Nephrology
– Urology
Hematuria Workup – Referral
„ Nephrology
suspected
referral if glomerular source
– Hx, UA, imaging studies support
– + FHx, Sx, HTN
– Proteinuria > 300 (some say 1000) mg/24hr
– RBC casts, acanthocytes
– High or rising creatinine
– ?Need for renal Bx? – may not matter if isolated
glomerular hematuria as management may be
the same regardless of cause
Hematuria Workup
„ Basic
workup before referral
– H&P!
– Lab
– Imaging
„ Referral
– Nephrology
– Urology
Hematuria Workup – Referral
„ Urology
referral if lower GU source
suspected
– Hx, UA, imaging studies support
– No Sx, proteinuria, abnormal cells on UA, nml
creatinine
– Tumor on imaging
– ?Need for cystoscopy? – usually indicated if nml
basic workup AND risk factors for bladder CA
Hematuria Workup
“Risk Factors” for CA
„
„
„
„
„
„
„
age > 40-50
cigarette smoking
occupational exposure to certain chemicals
(leather, dye, and rubber or tire manufacturing)
heavy phenacetin use
past Rx w/ high doses of cyclophosphamide
ingestion of aristolochic acid (found in some
herbal weight-loss preparations)
schistosomiasis
Hematuria Workup – Referral
Hematuria Workup – Summary
Hematuria Workup – Summary
Hematuria Workup – Summary
Hematuria Outline
„ Definition
„ Prevalence
„ Causes
„ Workup
„ Follow
up
Hematuria Follow up
„ Referral
for definitive Rx if cause found
„ If negative workup, follow up depends on
risk factors, presence of other Sx, age
„ In pts w/ a neg initial evaluation of
asymptomatic microscopic hematuria,
consider repeating urinalysis, voided urine
cytology and BP at 6, 12, 24 and 36 months
Hematuria Follow up
„ 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
Hematuria Follow up
„
Immediate urologic reevaluation, with
consideration of cystoscopy, cytology or repeat
imaging, should be performed if any of the
following occur:
– gross hematuria
– abnormal urinary cytology
– irritative voiding symptoms in the absence of infection
„
If none of these occurs within three years, the
patient does not require further urologic
monitoring
Hematuria Follow up - Summary
Hematuria Outline
„ Definition
„ Prevalence
„ Causes
„ Workup
„ Follow
up
References (following this slide)
Cohen RA, Brown RS. Microscopic
hematuria. N Engl J Med June 5,
2003;348:2330-8
2. Grossfeld et al Asymptomatic Microscopic
Hematuria in Adults: Summary of the AUA
Best Practice Policy Recommendations.
Am Fam Physician 2001;63:1145-54
3. UpToDate® 'Evaluation of hematuria in
adults'
1.
The
new england journal
of
medicine
clinical practice
Microscopic Hematuria
Robert A. Cohen, M.D., and Robert S. Brown, M.D.
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors’ clinical recommendations.
An otherwise healthy 48-year-old woman is found to have microscopic hematuria
(5 red cells per high-power field) on a urinalysis performed by a life insurance company. No other laboratory abnormalities are identified; the serum creatinine concentration is 0.8 mg per deciliter (70.7 µmol per liter). The woman reports no symptoms and
is a nonsmoker. Her blood pressure is 118/74 mm Hg, and the findings on physical
examination are normal. How should she be evaluated?
the clinical problem
From the Division of Nephrology, Department of Medicine, Beth Israel Deaconess
Medical Center and Harvard Medical
School, Boston. Address reprint requests
to Dr. Cohen at the Division of Nephrology,
Beth Israel Deaconess Medical Center, 330
Brookline Ave., DA517, Boston, MA 02115,
or at [email protected].
Microscopic hematuria without proteinuria is often an incidental finding. Since bleeding may arise from any site along the urinary tract, it has a broad differential diagnosis,
possibly reflecting an entirely benign cause, such as vigorous exercise just before urine
collection, or a malignant, potentially lethal disease, such as bladder or renal cancer.
Even with a thorough investigation, the source of the microscopic hematuria frequently is not found. We focus here on the evaluation of microscopic hematuria in persons
older than 18 years of age.
N Engl J Med 2003;348:2330-8.
Copyright © 2003 Massachusetts Medical Society.
definitions
We define microscopic hematuria as 2 or more red cells per high-power field on microscopical examination.1,2 Definitions vary, however, from 1 to more than 10 red cells per
high-power field.2 Dipstick testing for heme may be too sensitive, detecting hemoglobin from 1 or 2 red cells per high-power field. Such testing also lacks specificity, since
the presence of myoglobin or hemoglobin may result in a positive test when the urine
contains no red cells. Therefore, if the dipstick test is positive, the presence of red cells
should be confirmed by microscopical examination.
There have been only a few population-based studies addressing the prevalence of
microscopic hematuria, and their results vary according to the age and sex distribution
of the populations studied, whether the diagnosis was based on the dipstick test alone
or that test coupled with microscopical evaluation, and the number of screening tests
performed per patient. In six studies, the prevalence ranged from 0.18 percent to 16.1
percent.3,4 Only two studies report a higher prevalence among women than among
men.2 Although some studies suggest that there may be an increased prevalence among
older persons,2 others show no difference according to age.5
Microscopic hematuria also may be transient. In a study of male soldiers who underwent yearly examinations of urinary sediment over a 12-year period, the cumulative incidence was 39 percent with microscopic hematuria on one examination and 16 percent
with microscopic hematuria on two or more examinations.6 In another study, transient
microscopic hematuria was noted in about 13 percent of postmenopausal women.5
Transient microscopic hematuria may be caused by vigorous exercise before urine collection, by sexual intercourse, by mild trauma, or by menstrual contamination. There are
2330
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clinical practice
no data on differences between patients with transient microscopic hematuria and those with persistent microscopic hematuria with regard to the likelihood of underlying urinary tract disease.
clinical relevance
dye, and rubber or tire manufacturing), heavy phenacetin use, past treatment with high doses of cyclophosphamide, and ingestion of aristolochic acid
found in some herbal weight-loss preparations.11-13
strategies and evidence
Causes of isolated microscopic hematuria (without
proteinuria) are listed in Table 1 and can be classified as either glomerular or nonglomerular in origin. Because renal biopsies are not typically part of
the evaluation of microscopic hematuria, it is difficult to estimate the percentage of cases that are
clearly attributable to glomerular bleeding. In a
study involving 157 men in whom renal biopsy
was performed when no cause of microscopic hematuria had been identified by other tests, a glomerular source was identified in 16 percent of the
patients. IgA nephropathy, a form of glomerulonephritis defined histologically by glomerular IgA
deposits, accounted for the majority of cases with a
glomerular source.7 In a series of 165 patients, renal biopsies were performed after renal imaging
and cystoscopy. No abnormalities were noted on
renal biopsy in 87 patients. Of the remaining 78 patients, 49 had IgA nephropathy.8 Although IgA nephropathy is probably the most common glomerular cause of hematuria,9 some data suggest that thin
basement membrane disease, an inherited glomerular disorder defined histologically by diffuse thinning of the glomerular basement membranes, may
be as frequent a cause of isolated glomerular microscopic hematuria.10 Hereditary nephritis is a less
common glomerular cause.
Nonglomerular sources of microhematuria
involving the kidney and the upper urinary tract
include neoplasm, nephrolithiasis, cystic disease
(including polycystic kidney disease and medullary
sponge kidney), papillary necrosis, and metabolic
defects such as hypercalciuria or hyperuricosuria.
The causes involving the lower urinary tract include
disorders of the bladder, urethra, and prostate.
Urologic cancers (mainly of the bladder and
prostate) are estimated to account for about 5 percent of cases of microscopic hematuria, although
estimates vary widely according to whether the
study is referral-based (higher percentages) or
population-based (lower percentages).2 The risk
of bladder cancer increases significantly with age,
particularly after 65 years of age.11 Risk factors for
transitional-cell cancer of the bladder or urinary
tract include cigarette smoking, occupational exposure to chemicals used in certain industries (leather,
n engl j med 348;23
The first steps in evaluating microscopic hematuria should be to obtain a pertinent history and perform a physical examination. It should be noted that
anticoagulant therapy alone does not cause hematuria, except in the case of a marked overdose of
warfarin.14 The urine should be evaluated for bacteriuria and pyuria. If either is present, a urine culture should be ordered. Serum creatinine should
be measured to evaluate the patient for renal insufficiency. If proteinuria is detected on dipstick testing, the ratio of the urinary protein concentration to
the urinary creatinine concentration, in milligrams
per deciliter, should be determined, or a 24-hour
urine collection should be obtained for measurement of total protein excretion. Clinically significant proteinuria (a ratio of urinary protein to urinary creatinine of more than 0.3 or 24-hour urinary
protein excretion of more than 300 mg) points to
the kidney as a source of microscopic hematuria.
urinalysis
The single most important test in the evaluation of
hematuria is the microscopical analysis of urine,
because it often distinguishes glomerular from
nonglomerular bleeding (Fig. 1). If the findings indicate a glomerular site of bleeding, no urologic
evaluation is necessary. Documentation of renal insufficiency or proteinuria warrants referral to a nephrologist for evaluation and possible renal biopsy;
referral should be prompt if a second measurement
of serum creatinine is abnormal or higher than the
first. However, renal biopsy in a patient with microscopic hematuria unaccompanied by clinically significant proteinuria or renal insufficiency is not
supported by the limited data that are available. In
a study involving 75 patients with isolated microscopic hematuria who underwent renal biopsy, 36
percent had thin basement membrane disease, and
23 percent had IgA nephropathy — findings that
made little difference in their care.20
imaging of the upper urinary tract
If a glomerular source is ruled out or considered
unlikely on the basis of the clinical presentation, the
upper urinary tract should be imaged. The goal is to
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Table 1. Causes of Isolated Microscopic Hematuria.*
Origin
<50 Yr of Age
Glomerular
≥50 Yr of Age
IgA nephropathy (increased incidence in
Asians)
IgA nephropathy
Thin basement membrane disease (benign
familial hematuria)
Hereditary nephritis (Alport’s syndrome)
Hereditary nephritis (Alport’s syndrome)
Mild focal glomerulonephritis of other
causes
Mild focal glomerulonephritis of other causes
Nonglomerular
Upper urinary tract causes
Nephrolithiasis
Nephrolithiasis
Pyelonephritis
Renal-cell cancer
Polycystic kidney disease
Polycystic kidney disease
Medullary sponge kidney
Pyelonephritis
Hypercalciuria, hyperuricosuria, or both,
without documented stones
Renal-pelvis or ureteral transitional-cell
cancer
Renal trauma
Papillary necrosis
Papillary necrosis
Renal infarction
Ureteral stricture and hydronephrosis
Ureteral stricture and hydronephrosis
Sickle cell trait or disease in blacks
Renal tuberculosis
Renal infarction or arteriovenous malformation
Renal tuberculosis in endemic areas or in
patients with HIV infection
Lower urinary tract causes
Cystitis, prostatitis, and urethritis
Cystitis, prostatitis, and urethritis
Benign bladder and ureteral polyps and tumors
Bladder cancer
Bladder cancer
Prostate cancer
Prostate cancer
Benign bladder and ureteral polyps
and tumors
Urethral and meatal strictures
Schistosoma haematobium in North Africans
Uncertain
Exercise hematuria
Exercise hematuria
“Benign hematuria” (unexplained microscopic
hematuria)
Over-anticoagulation (usually with
warfarin)
Over-anticoagulation (usually with warfarin)
Factitious hematuria (usually presents
with gross hematuria)
* Disorders causing microhematuria are presented roughly in order of descending frequency of presentation, according to
available data. HIV denotes human immunodeficiency virus.
detect any neoplasms, including renal-cell carcinoma and the less prevalent transitional-cell carcinomas of the renal pelvis and ureters, urolithiasis,
cystic disease, and obstructive lesions. Excretory
urography has been used routinely to examine the
upper urinary tract in most studies of microscopic
2332
n engl j med 348;23
hematuria.2 Ultrasonography is safer, does not involve exposure to intravenous radiographic contrast
medium, is appropriate for use during pregnancy,
and is less expensive.21 Ultrasonography, however,
may be limited in its detection of solid tumors that
are less than 3 cm in diameter.22 In a study in which
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clinical practice
enhanced computed tomography (CT) was used as
the standard, the sensitivity and specificity of ultrasonography for the detection of renal parenchymal
masses between 2 and 3 cm in diameter were 82 percent and 91 percent, respectively. In the same study,
the sensitivity and specificity of excretory urography were 52 percent and 82 percent, respectively.23
Since excretory urography may miss small renal
masses and sometimes cannot differentiate solid
from cystic masses, a follow-up study with the use
of ultrasonography, CT, or magnetic resonance imaging is often ordered. To our knowledge, no studies have specifically compared the effectiveness of
these various imaging techniques in the evaluation
of microscopic hematuria.
A CT scan without the use of a contrast agent is
Figure 1. Findings in Urinary Sediment.
In Panel A (¬ 440), urinary sediment shows a red-cell
cast and red cells. Red-cell casts indicate the presence
of glomerular bleeding, a finding that is very specific
but rather insensitive. If no red-cell casts are found,
urinary red-cell morphology should be examined. The
small, dysmorphic red cell (arrow) suggests a glomerular source,15 and the uniform, biconcave disk shape of
normal red cells (arrowhead) suggests nonglomerular
bleeding. Some have noted that dysmorphic or abnormally shaped red cells are not reliable enough as a
means for distinguishing a glomerular source of bleeding from a nonglomerular source, particularly if mixtures
of dysmorphic and normal-appearing red cells are
seen.16,17 (Photomicrograph courtesy of the late Dr.
Richard Nesson.) In Panel B (¬ 440), urinary sediment
shows normal red cells (arrow) and crenated red-cell
forms with spicules (arrowhead). Crenated red cells
form in concentrated urine and are not diagnostically
relevant. A more specific finding with bleeding of glomerular origin may be the presence of a particular form
of abnormal red cells in the urine — acanthocytes,18,19
doughnut-like cells with membrane blebs attached
(Panel C, ¬ 440, arrowhead). With meaningful acanthocyturia defined as the presence of acanthocytes accounting for more than 5 percent of urinary red cells,
the sensitivity of phase microscopy for detecting glomerular hematuria was 52 percent in one large series in
which glomerulonephritis was documented with renal
biopsy and 73 percent in another series, and the specificity for detecting a glomerular source was 98 percent
and 100 percent, respectively, in the two series.18,19 The
sensitivity and specificity of light microscopy for identifying acanthocytes have not been reported; since most
laboratories do not routinely identify acanthocytes, this
test should ideally be performed by an experienced laboratory technologist alerted to look for acanthocytes or
by a nephrologist.
n engl j med 348;23
appropriate as the first test for patients with suspected stone disease. In one series of patients with
renal colic who underwent unenhanced helical CT
followed immediately by excretory urography, the
sensitivity for the detection of ureteral stones was
100 percent with the former, as compared with 67
percent with the latter.24 When there is no clinical
suspicion of stone disease, CT urography should be
performed first without contrast medium and then
with it, particularly in patients who might be at increased risk for kidney cancer. Although CT is more
expensive than excretory urography or ultrasonography, studies involving the latter techniques are
often followed by additional imaging (to confirm
that cysts are benign or to reevaluate questionable
or negative studies) and thus cannot be considered
A
B
C
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new england journal
cost-saving in general. If CT is unavailable or prohibitively expensive, excretory urography, ultrasonography, or the combination of the two is a reasonable alternative. If a mass suspected to be malignant
is identified, the patient should be referred to a urologist. If polycystic kidney disease is found, the patient should be referred to a nephrologist.
evaluation of the lower urinary tract
The source of microscopic hematuria remains obscure in about 70 percent of cases after imaging of
the upper urinary tract and examination of urine for
evidence of glomerular hematuria. In these cases, it
may be necessary to evaluate the lower urinary tract,
with particular attention to possible bladder cancer.
Cystoscopy is appropriate if risk factors for bladder
cancer are present. This procedure is also warranted in older men with asymptomatic microscopic
hematuria, but the data are inconclusive regarding
the age at which to recommend cystoscopy.
In one community-based study,25 1340 men 50
years of age or older (mean age, 65 years) were tested for hematuria with urinary dipsticks daily for two
weeks. Twenty-one percent had at least one episode
of hematuria. Of these men, 192 underwent complete urologic evaluation. A total of 16 malignant
lesions were identified: 9 bladder cancers, 1 renalcell carcinoma, and 6 prostate cancers. In another
community-based study, 3152 men older than 60
years of age were screened for microscopic hematuria by urinary dipstick testing daily or weekly for
10 weeks. Twenty percent had hematuria on at least
one dipstick test, and of the 319 men who underwent full urologic evaluation, 22 had cancer (bladder
cancer in 17 and prostate cancer in 5).26 Thirteen
of the 17 men with bladder cancer had a history of
cigarette smoking. In these two studies, the positive predictive value of dipstick testing for the detection of bladder cancer was 4.7 percent and 5.3
percent, respectively. In a referral-based study involving 100 men younger than 40 years of age with
microscopic hematuria, no bladder cancers were
identified by cystoscopy.27 CT studies with the use
of radiographic contrast medium may reduce the
need for cystoscopy. In a recent series, the sensitivity of this technique was 100 percent and the specificity was 98 percent for the detection of neoplasms
of the bladder.28
Available data provide less support for cystoscopy in women with asymptomatic microscopic
hematuria than in men. No cases of bladder cancer
were found in one prospective, referral-based study
2334
n engl j med 348;23
of
medicine
involving 177 women (mean age, 57.2 years) with
asymptomatic microscopic hematuria who underwent cystoscopy.29 In another referral-based study,
involving 1034 adults (75 percent of whom were female), only two cases of bladder cancer were identified in women with microscopic hematuria (one
54 years old and the other 70 years old).30 In contrast, in a referral-based study involving 484 women with microscopic hematuria, 12 cases of urologic cancer were identified in women between 60 and
89 years of age, and 5 cases were found in women
between 40 and 59 years of age. The specific types
of cancer and the number of diagnoses made with
cystoscopy were unclear.31
cytologic studies of urine
Cytologic analysis of voided urine is less sensitive
(66 percent and 79 percent in two large series) than
cystoscopy in the detection of bladder cancer32,33
but has high specificity (95 percent and 100 percent in the two series). The sensitivity is improved
if specimens of urine from the first voiding in the
morning on three consecutive days are obtained.34
The sensitivity is higher for the detection of highgrade bladder cancer and carcinoma in situ33 but
lower for the detection of cancers of low histologic
grade, and cytologic analysis is insensitive for the
detection of renal-cell cancer. Cystoscopy itself had
87 percent sensitivity for the detection of bladder
cancer in one large series and is especially limited
for the diagnosis of carcinoma in situ.32 Urinary
molecular markers for the noninvasive detection of
bladder cancer are currently being evaluated but
have not yet been validated.35
follow-up after negative evaluation
A thorough evaluation of the urinary system may fail
to identify a source of microscopic hematuria. In
studies in which both imaging of the upper urinary
tract and cystoscopy were performed in patients with
microscopic hematuria, a source was not identified in 19 to 68 percent of the patients evaluated.29,31,36-39 Microscopy was not routinely part of
the evaluation in these studies, suggesting that more
glomerular causes of microscopic hematuria might
be identified with this addition.
Follow-up of patients with unexplained microscopic hematuria has been evaluated in two studies,
both without a control group. In one, 191 patients
with asymptomatic hematuria that remained unexplained after urologic evaluation with urinalysis,
cytologic analysis of voided urine, excretory urog-
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clinical practice
raphy, and cystoscopy subsequently underwent excretory urography and cystoscopy. No cancers were
detected during follow-up, prompting the authors
to suggest that no further studies are necessary unless symptoms develop.40 This suggestion was corroborated by similar recommendations in another
prospective study.31
areas of uncertainty
Currently, the data are inadequate to support clearcut recommendations regarding the evaluation and
management of microscopic hematuria. Shortcomings of available studies include inconsistencies in
definition, study design, selection criteria, and diagnostic-test techniques and procedures used.41 Data
are lacking on outcomes in patients with microscopic hematuria who did not undergo formal evaluation and those in whom the finding remained
unexplained despite evaluation. In addition, there
have been no randomized trials comparing the outcomes associated with different strategies.
guidelines
The U.S. Preventive Services Task Force and the Canadian Task Force on the Periodic Health Examination do not recommend routine screening of urine
for microscopic hematuria.11 Regarding bladder
cancer, they cite the low predictive value of a positive screening test even in a high-risk population
of older adults. They also cite the absence of proof
that early detection improves the prognosis in the
small number of patients found to have urinary tract
cancer.11
The American Urological Association has issued
guidelines for the evaluation of microscopic hematuria in adults (http://www.aafp.org/afp/20010315/
1145.html). According to these guidelines, after
microscopical examination of the urine, testing for
proteinuria, and measurement of serum creatinine,
a full urologic workup should be performed, including radiologic imaging of the upper urinary tract,
cytologic analysis of urine, and cystoscopy (recommended for all persons with asymptomatic microscopic hematuria who are older than 40 years).42
conclusions
and recommendations
When asymptomatic microscopic hematuria is detected, as in the patient described in the vignette, the
n engl j med 348;23
urinalysis should be repeated a few days later before any workup is initiated, especially if the patient
has had vigorous exercise, menstruation, trauma to
the urinary tract, or sexual activity just before the
collection. Our recommended approach after a second urinalysis is summarized in Figure 2.
If microscopic hematuria is absent on repeated
testing, we do not recommend further evaluation,
unless the patient has risk factors for bladder cancer or transitional-cell cancer of the urinary tract,
such as cigarette smoking or exposure to toxins. If
repeated urinalysis confirms the presence of microscopic hematuria, we recommend microscopical
analysis for evidence of a glomerular source, such
as acanthocyturia or red-cell casts. Whether or not
such a source is found, if microscopic hematuria is
accompanied by proteinuria or renal insufficiency,
the patient should be referred to a nephrologist for
evaluation.
If isolated glomerular microscopic hematuria is
identified, we recommend follow-up by a primary
care physician, initially at six months and then annually, to check for the development of proteinuria
or renal insufficiency (although there are no data
supporting a specific interval between follow-up
visits). We would not perform a renal biopsy in a patient with isolated glomerular microscopic hematuria, since the limited data available do not suggest
that identification of the specific disease makes any
difference in management or outcome.
If examination of urine does not suggest a glomerular source and the patient is not pregnant, helical CT urography should be performed, first without and then with radiographic contrast medium,
primarily for the detection of occult stone disease
or a mass (in the upper urinary tract or possibly in
the bladder). An examination without contrast medium would be appropriate if stone disease was
suspected clinically. CT is highly sensitive for the
detection of disease in the upper urinary tract; we
do not recommend excretory urography unless CT
is unavailable or deemed too expensive. Ultrasonography can be performed in place of CT (and is
advised for patients with renal failure, pregnancy,
or hypersensitivity to contrast medium), with the understanding that further imaging may be necessary.
If imaging is unrevealing, we recommend obtaining specimens of urine from the first voiding
in the morning on three consecutive days for cytologic analysis in persons older than 40 years of
age, but the insensitivity of cytologic analysis for
the detection of low-grade bladder cancer should
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2335
The
new england journal
of
medicine
Urine dipstick test positive
for microscopic heme
Repeated urine dipstick
testing (several days later)
¡
Workup ends (unless
there are risk factors
for bladder cancer)
¡
Evaluation for
hemoglobinuria
or myoglobinuria
+
Microscopical examination
of urine
Acanthocytes or
red-cell casts
Isomorphic red cells
Glomerular hematuria
Nonglomerular hematuria
Isolated microscopic
hematuria
Proteinuria or renal
insufficiency
Helical CT
+
Referral based
on lesion
+
Cystoscopy
¡
Periodic medical follow-up
(for onset of proteinuria
or renal insufficiency)
Nephrology referral
Cytologic analysis of urine
(3 serial first morning
specimens)
¡
≥50 Yr of age or risk factors
for bladder cancer
<50 Yr of age without risk
factors for bladder cancer
Cystoscopy
Workup ends
Figure 2. Evaluation of Microscopic Hematuria.
If hematuria is determined to be nonglomerular in origin, computed tomography (CT) should be performed without
contrast medium if a stone is suspected to be present or first without and then with contrast medium if no stone is suspected. Ultrasonography should be performed instead of CT in pregnant patients and those with hypersensitivity to contrast medium. Risk factors for bladder cancer include cigarette smoking, occupational exposure to chemicals used in
certain industries (leather, dye, and rubber or tire manufacturing), heavy phenacetin use, past treatment with high doses
of cyclophosphamide, and ingestion of aristolochic acid found in some herbal weight-loss preparations. Plus signs indicate positive findings, and minus signs negative findings.
2336
n engl j med 348;23
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Copyright © 2003 Massachusetts Medical Society. All rights reserved.
clinical practice
be recognized. Cystoscopy should be performed if
cytologic analysis of voided urine has identified
neoplastic cells or if the patient has risk factors for
bladder cancer. In the absence of these factors, the
question of the age at which cystoscopy should routinely be performed to evaluate patients of either sex
who have microscopic hematuria remains controversial. At variance with the American Urological
Association, we would not routinely recommend
cystoscopy for all persons older than 40 years of
age, since we believe that such a recommendation
would lead to unnecessary testing, with the attendant expense and potential risks associated with this
invasive procedure; we would, however, recommend yearly follow-up with urinalysis. Recognizing
the trend toward a higher incidence of bladder cancer with advancing age, we would advise men and
women older than 50 years of age who have persistent microscopic hematuria to undergo cystoscopy.
Cystoscopy is also recommended if gross hematuria
develops, because this finding is associated with a
higher risk of urologic cancer than is microscopic
hematuria.2,31
We are indebted to Isaac Stillman, M.D., for his help in producing
the photomicrographs; to Susan Cohen and Sven Paulen, M.D., for
assistance in the translation of a Swedish manuscript; and to Thomasina Shavers for assistance in the preparation of the manuscript.
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2. Sutton JM. Evaluation of hematuria in
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8. Topham PS, Harper SJ, Furness PN, Harris KPG, Walls J, Feehally J. Glomerular disease as a cause of isolated microscopic haematuria. Q J Med 1994;87:329-35.
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13. Talar-Williams C, Hijazi YM, Walther
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14. Van Savage JG, Fried FA. Anticoagulant
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15. Birch DF, Fairley KF. Haematuria: glomerular or non-glomerular? Lancet 1979;2:
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16. Pollock C, Lui P-L, Gyory AZ, et al. Dysmorphism of urinary red blood cells — value
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17. Offringa M, Benbassat J. The value of
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18. Kohler H, Wandel E, Brunck B. Acanthocyturia — a characteristic marker for
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19. Kitamoto Y, Tomita M, Akamine M, et al.
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20. McGregor DO, Lynn KL, Bailey RR,
Robson RA, Gardner J. Clinical audit of the
use of renal biopsy in the management of
isolated microscopic hematuria. Clin Nephrol 1998;49:345-8.
21. Corwin HL, Silverstein MD. The diagnosis of neoplasia in patients with asymptomatic microscopic hematuria: a decision
analysis. J Urol 1988;139:1002-6. [Erratum,
J Urol 1988;140:1558.]
22. Jamis-Dow CA, Choyke PL, Jennings SB,
Linehan WM, Thakore KN, Walther MM.
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24. Sourtzis S, Thibeau JF, Damry N, Raslan
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AJR Am J Roentgenol 1999;172:1491-4.
25. Messing EM, Young TB, Hunt VB, et al.
Home screening for hematuria: results of a
multiclinic study. J Urol 1992;148:289-92.
26. Britton PJ, Dowell AC, Whelan P, Harris
CM. A community study of bladder cancer
screening by the detection of occult urinary
bleeding. J Urol 1992;148:788-90.
27. Jones DJ, Langstaff RJ, Holt SD, Morgans BT. The value of cystourethroscopy in
the investigation of microscopic haematuria in adult males under 40 years: a prospective study of 100 patients. Br J Urol
1988;62:541-5.
28. Lang EK, Macchia RJ, Thomas R, et al.
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29. Bard RH. The significance of asymptomatic microhematuria in women and its economic implications: a ten-year study. Arch
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30. Murakami S, Igarashi T, Hara S, Shimazaki J. Strategies for asymptomatic microscopic hematuria: a prospective study of
1,034 patients. J Urol 1990;144:99-101.
31. Khadra MH, Pickard RS, Charlton M,
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32. Rife CC, Farrow GM, Utz DC. Urine
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33. Koss LG, Deitch D, Ramanathan R, Sherman AB. Diagnostic value of cytology of
voided urine. Acta Cytol 1985;29:810-6.
34. Badalament RA, Hermansen DK, Kimmel M, et al. The sensitivity of bladder wash
flow cytometry, bladder wash cytology, and
voided cytology in the detection of bladder
carcinoma. Cancer 1987;60:1423-7.
35. Stein JP, Grossfeld GD, Ginsberg DA, et
al. Prognostic markers in bladder cancer:
a contemporary review of the literature. J Urol
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with asymptomatic microhematuria. JAMA
1956;161:610-3.
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38. Davides KC, King LM, Jacobs D. Management of microscopic hematuria: twentyfour-year experience with 150 cases in a community hospital. Urology 1986;28:453-5.
39. Ritchie CD, Bevan EA, Collier SJ. Impor-
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40. Howard RS, Golin AL. Long-term followup of asymptomatic microhematuria.
J Urol 1991;145:335-6.
41. Köhler C, Varenhorst E. Mikroskopisk
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follow-up. Urology 2001;57:604-10.
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Copyright © 2003 Massachusetts Medical Society. All rights reserved.
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.)
B
lood 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 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
MARCH 15, 2001 / VOLUME 63, NUMBER 6
www.aafp.org/afp
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
AMERICAN FAMILY PHYSICIAN
1145
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.
hematuria by the dipstick method should be
confirmed by microscopic evaluation of urinary sediment.5-8
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 high-power 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
1146
AMERICAN FAMILY PHYSICIAN
www.aafp.org/afp
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 followup. Urology 2001;57(4) (In press).
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: lifethreatening; 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 referral-based populations. A cause for asymptomatic microscopic
VOLUME 63, NUMBER 6 / MARCH 15, 2001
Hematuria
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.
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.
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 facMARCH 15, 2001 / VOLUME 63, NUMBER 6
tors 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 doughnutshaped red blood cells are generally due to
lower urinary tract bleeding. Accurate determination of red blood cell morphology may
require inverted phase contrast microscopy.
www.aafp.org/afp
AMERICAN FAMILY PHYSICIAN
1147
Initial Evaluation of Asymptomatic Microscopic Hematuria*
Patient with newly diagnosed asymptomatic microscopic hematuria
Exclude benign causes, including menstruation, vigorous
exercise, sexual activity, viral illness, trauma and infection.
If one or more of the following are present:
Microscopic hematuria accompanied by
significant proteinuria†
Dysmorphic red blood cells or red cell casts
Elevated serum creatinine level (based on
normal reference ranges for men and women)
Evaluation for primary renal disease
If conditions suggestive of primary renal disease are
not present (i.e., normal creatinine level, absence of
proteinuria, absence of dysmorphic red blood cells or
red cells casts), or if any of the following are present:
Smoking history
Occupational exposure to chemicals or dyes
(benzenes or aromatic amines)
History of gross hematuria
Age > 40 years
Previous urologic disorder or disease
History of irritative voiding symptoms
History of recurrent urinary tract infection despite
appropriate use of antibiotics
Urologic evaluation (see Figure 2)
*—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).
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.
1148
AMERICAN FAMILY PHYSICIAN
www.aafp.org/afp
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
VOLUME 63, NUMBER 6 / MARCH 15, 2001
Hematuria
Urologic Evaluation of Asymptomatic Microscopic Hematuria
Patient without conditions suggestive of primary renal disease
Low-risk patient:
Age < 40 years
No smoking history
No history of chemical exposure
No irritative voiding symptoms
No history of gross hematuria
No history of urologic disorder
or disease
High-risk patients
Complete evaluation
(upper tract imaging,
cytology, cystoscopy)
Upper tract imaging
Cytology
Cystoscopy
Negative
Positive, atypical
or suspicious
Negative
Cystoscopy
Negative
Positive
Positive
Treat
Treat
Negative
Urinalysis, blood pressure and cytology
at 6, 12, 24 and 36 months
Consider
Negative for 3 years
Persistent hematuria,
hypertension, proteinuria,
glomerular bleeding
No further urologic
monitoring
Evaluate for primary
renal disease.
Positive
Gross hematuria,
abnormal cytology,
irritative voiding
symptoms without
infection
Treat
Repeat complete
evaluation.
Glomerular bleeding
or proteinuria
Isolated hematuria
Renal biopsy
Biopsy controversial
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).
MARCH 15, 2001 / VOLUME 63, NUMBER 6
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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.
and crescentic glomerulonephritis. In addition, interstitial renal disease, such as druginduced 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.
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In women, urethral and vaginal examinations should be performed to exclude local
causes of microscopic hematuria. A catheterized urinary specimen is indicated if a cleancatch 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.
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.
VOLUME 63, NUMBER 6 / MARCH 15, 2001
Hematuria
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.
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
MARCH 15, 2001 / VOLUME 63, NUMBER 6
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.
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
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
Best modality for evaluation of urinary stones, renal and
perirenal infections, and associated complications
Sensitivity of 94 % to 98 % for detection of renal stones,
compared with 52% to 59% for intravenous urography
and 19% for ultrasonography
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).
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AMERICAN FAMILY PHYSICIAN
1151
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 avail-
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 SloanKettering 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.
Address correspondence to Carol Schwartz, M.P.H., R.D., Guidelines Manager, American Urological Association, 1120 N. Charles St., Baltimore, MD 21201-5559 (e-mail:
[email protected]). Reprints are not available from the authors .
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able) can be performed at the end of the CT
examination to assess the ureters and bladder
in an IVU–like 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 highVOLUME 63, NUMBER 6 / MARCH 15, 2001
Hematuria
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.
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 lowgrade 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.
MARCH 15, 2001 / VOLUME 63, NUMBER 6
Computed tomography is the best imaging modality for the
evaluation of urinary stones, renal and perirenal infections,
and associated complications.
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15. Carson CC 3d, Segura JW, Greene LF. Clinical
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16. Davides KC, King LM, Jacobs D. Management of
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with 150 cases in a community hospital. Urology
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Schumann GB, Greenberg RA. Evaluation of asymptomatic microhematuria. Urology 1995;46:484-9.
18. Greene LF, O’Shaughnessey EJ, Hendricks ED.
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33. Sparwasser C, Cimniak HU, Treiber U, Pust RA. Significance of the evaluation of asymptomatic microscopic haematuria in young men. Br J Urol 1994;
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34. Clayman RV, Reddy P, Lange PH. Flexible fiberoptic
and rigid-rod lens endoscopy of the lower urinary
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1984;131:715-6.
35. Denholm SW, Conn IG, Newsam JE, Chisholm GD.
Morbidity following cystoscopy: comparison of
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36. Flannigan GM, Gelister JS, Noble JG, Milroy EJ.
Rigid versus flexible cystoscopy. A controlled trial of
patient tolerance. Br J Urol 1988;62:537-40.
37. Pavone-Macaluso M, Lamartina M, Pavone C,
Vella M. The flexible cystoscope. Int Urol Nephrol
1992;24:239-42.
38. Hiatt RA, Ordonez JD. Dipstick urinalysis screening,
asymptomatic microhematuria, and subsequent
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[Published erratum appears in Cancer Epidemiol
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Evaluation of hematuria in adults
Burton D Rose, MD
Robert H Fletcher, MD
UpToDate performs a continuous review of over 300 journals and other resources. Updates
are added as important new information is published. The literature review for version 11.3
is current through September 2003; this topic was last changed on March 19, 2002. The
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Hematuria that is not explained by an obvious condition (eg, cystitis) is relatively common.
As an example, one study of 231 men over the age of 50, who were tested weekly for three
months, found that hematuria was present in 10 percent [1].
Hematuria itself is not dangerous unless extraglomerular bleeding is so brisk that it causes
clots that obstruct the ureter(s). However, the finding of hematuria is important, since it
may be a symptom of an underlying serious condition. In the example noted above, of the
23 patients with hematuria, five were found to have cancers involving the urinary tract, and
another five had underlying medical disorders requiring immediate treatment [1].
DEFINITION OF HEMATURIA — Hematuria may be grossly visible or microscopic.
Gross hematuria — Gross hematuria is suspected because of the presence of red or brown
urine. The color change does not necessarily reflect the degree of blood loss, since as little
as 1 mL of blood per liter of urine can induce a visible color change. In addition, the
intermittent excretion of red to brown urine can be seen in a variety of clinical settings other
than blood loss. (See "Red urine: Hematuria, hemoglobinuria; myoglobinuria").
Thus, the initial step in the evaluation of patients with red urine is centrifugation of the
specimen to see if the red color is in the urine sediment or the supernatant (show figure 1).
As contamination with blood is a possibility in menstruating and post-partum women, urine
for analysis is best obtained when the bleeding has ceased. If this is not possible, a tampon
can be inserted, and urinalysis obtained after the perineum is thoroughly cleansed.
Hematuria is responsible if the red color is seen only in the urine sediment, with the
supernatant being clear.
If, on the other hand, it is the supernatant that is red, then the supernatant should be
tested for heme with a urine dipstick.
A red supernatant that is negative for heme is a rare finding that can be seen in several
conditions, including porphyria (show figure 2). (See "Understanding the porphyrias",
section on Urine porphyrin analysis). Other causes include the use of the bladder analgesic
phenazopyridine, and the ingestion of beets in susceptible subjects. (See "Red urine:
Hematuria, hemoglobinuria; myoglobinuria", section on Beeturia).
A red supernatant that is positive for heme is due to myoglobinuria or hemoglobinuria.
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Microscopic hematuria — Microscopic hematuria may be discovered by accident when
blood (either red blood cells or hemoglobin) is found on a urinalysis or dipstick done for
other purposes. Although hematuria is commonly defined as the presence of more than 2
RBCs per high power field in a spun urine sediment, there is no "safe" lower limit below
which significant disease can be excluded (show sediment 1) [2]. Lowering the cut-off value
of RBCs chosen to define hematuria results in a greater number of false positive test results
(eg, no underlying abnormality is found). On the other hand, if higher cut-off values are
chosen, it is more likely that the test will miss the presence of significant abnormalities.
The urine sediment is the gold standard for the detection of microscopic hematuria.
Dipsticks for hemoglobin detect 1 to 2 RBCs per high powered field and are therefore at
least as sensitive as urine sediment examination, but result in more false positive tests. In
comparison, false negative tests are unusual; as a result, a negative dipstick reliably
excludes abnormal hematuria [3]. Although red cells may be lysed in dilute urine, their
hemoglobin content will still be detected by the dipstick method.
ETIOLOGY — Hematuria may be a symptom of an underlying disease, some of which are
life threatening or treatable. The causes vary with age with the most common being
inflammation or infection of the prostate or bladder, stones, and, in older patients,
malignancy or benign prostatic hyperplasia (show figure 3) [2,4,5].
INITIAL EVALUATION — The initial evaluation of hematuria usually does not require the
participation of a subspecialist (nephrologist or urologist). This evaluation should address
the following three questions:
Are there any clues from the history or physical examination that suggest a particular
diagnosis?
Does the hematuria represent glomerular or extraglomerular bleeding?
Is the hematuria transient or persistent?
Historical clues — There are often clues from the history that point toward a specific
diagnosis. These include:
Concurrent pyuria and dysuria, which are usually indicative of a urinary tract infection.
A recent upper respiratory infection, suggesting either postinfectious glomerulonephritis
or IgA nephropathy (see "Hematuria following an upper respiratory infection").
A positive family history of renal disease, as in hereditary nephritis or polycystic kidney
disease.
Unilateral flank pain, which may radiate to the groin, suggesting ureteral obstruction due
to a calculus or blood clot. Flank pain that is persistent or recurrent can also occur in the
rare loin pain hematuria syndrome (see below).
Symptoms of prostatic obstruction in older men such as hesitancy and dribbling. The
cellular proliferation in benign prostatic hyperplasia (BPH) is associated with increased
vascularity, and the new vessels can be fragile. There is some controversy about whether
hematuria is more common in these patients than in age-matched controls [6,7]. However,
there is general agreement that the presence of BPH should not dissuade the clinician from
pursuing further evaluation of hematuria, particularly since older men are more likely to
have more serious disorders such as cancer of the prostate or bladder. Among those with
gross hematuria in whom no other cause can be identified, finasteride usually suppresses
the hematuria [8,9]. (See "Treatment of benign prostatic hyperplasia").
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Recent vigorous exercise or trauma (see "Exercise-induced hematuria").
History of a bleeding disorder or bleeding from multiple sites due to uncontrolled
anticoagulant therapy. In contrast, it should not be assumed that hematuria alone can be
explained by chronic warfarin therapy. In one report of 243 patients prospectively followed
for two years, the incidence of hematuria was similar to that in a control group not receiving
warfarin [10]. Furthermore, evaluation of patients who developed hematuria revealed a
genitourinary cause in 81 percent of cases. Infection was most common, but papillary
necrosis, renal cysts, and several malignancies of the bladder were also found. A smaller
study found significant urinary tract disease in nine of 30 patients, two of whom had bladder
cancer [11]. These observations indicate that hematuria in an anticoagulated patient should
generally be evaluated in the same fashion as in other patients unless there is evidence of
bleeding from multiple sites with markedly abnormal coagulation studies.
Cyclic hematuria in women that is most prominent during and shortly after menstruation,
suggesting endometriosis of the urinary tract [12]. Contamination with menstrual blood is
always a possibility, and should be ruled out by repeating the urinalysis when menstruation
has ceased.
Medications that might cause nephritis (usually with other findings, typically with renal
insufficiency).
In addition, black patients should be screened for sickle cell trait or disease, which can lead
to papillary necrosis and hematuria, (See "Renal manifestations of sickle cell disease").
Glomerular versus extraglomerular bleeding — The identification of the glomeruli as
the source of bleeding is important both prognostically and to optimize the subsequent
evaluation. In particular, patients with clear evidence of glomerular hematuria do not need
to be evaluated for potentially serious urologic disease [13].
Signs of glomerular bleeding include red cell casts (essentially pathognomonic for
glomerular disease), protein excretion exceeding 500 mg/day at a time when there is no
gross bleeding, most red cells having a dysmorphic appearance, and brown, cola-colored
urine (show table 1 and show sediment 2A-2C). (See "Hematuria: Glomerular versus
extraglomerular bleeding"). Although helpful if present, the absence of these findings does
not exclude glomerular disease. An additional important abnormality that may be seen is
blood clots. Clots virtually never occur in glomerular disease, perhaps due to the presence
of urokinase and tissue-type plasminogen activators in the glomeruli and in the renal
tubules.
Three tube test — In addition to the routine urinalysis, a three-tube test may also help to
locate the source of bleeding in selected cases. This test involves the collection and
comparative evaluation of three different urine specimens of roughly equal volume: the first
few mL; a mid-stream sample; and the last few mL. A urethral lesion is most likely if the
hematuria primarily occurs in the first sample, whereas a lesion near the bladder trigone is
most likely with terminal hematuria. Renal, ureteric, and diffuse bladder lesions result in
equivalent degrees of hematuria in each of the three specimens. Similar information can on
occasion be obtained from the history in patients with gross hematuria.
Role of renal biopsy — Although any glomerular disease may be associated with
hematuria, most patients also have other signs such as proteinuria, red cell casts, or renal
insufficiency. When persistent hematuria is essentially the only manifestation of glomerular
disease, one of three disorders is most likely: (1) IgA nephropathy, in which there is often
gross hematuria but a negative family history of renal disease; (2) hereditary nephritis, in
which gross hematuria can occur in association with a positive family history of renal failure;
and (3) thin basement membrane disease (also called benign familial hematuria), in which
gross hematuria is unusual and the family history may be positive for microscopic hematuria
but not for renal failure [14]. (See "Glomerular hematuria: IgA; Alport; thin basement
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membrane disease").
One of these three conditions is present in more than one-half of adults with isolated
hematuria and a negative radiologic and cystoscopic evaluation [14]. (See "Unexplained
hematuria" below). Postinfectious glomerulonephritis and exercise also can induce isolated
glomerular bleeding; however, the hematuria in these settings is typically transient, not
persistent as in the above disorders. (See "Hematuria following an upper respiratory
infection" and see "Exercise-induced hematuria").
Patients with glomerular hematuria should be referred to a nephrologist; they are likely to
be more experienced at examining urine sediment and can make a decision regarding the
need for renal biopsy. A biopsy is not usually performed for isolated glomerular hematuria,
since there is no specific therapy for any of these conditions.
The lack of utility of a renal biopsy in this setting is supported by a study of 111 patients
presenting with isolated hematuria in whom 75 underwent renal biopsy [15]. Follow-up of
85 patients at 43 months revealed that three patients had developed proteinuria (two with
IgA nephropathy and one without a biopsy), one had proteinuria and renal insufficiency
(membranoproliferative glomerulonephritis), and 11 were hypertensive (three with thin
basement membrane disease, two with IgA nephropathy, two with normal results, one with
focal glomerular sclerosis, and three without biopsy). The management of these patients
was rarely affected by the biopsy results.
However, biopsy should be considered if there is evidence of progressive disease as
manifested by an elevation in the plasma creatinine concentration, increasing protein
excretion, or an otherwise unexplained rise in blood pressure, even when the values remain
within the normal range [16].
Transient or persistent hematuria — No cause of low-level hematuria, in the absence of
other signs and symptoms, requires immediate diagnosis. Thus, it is reasonable to repeat
an abnormal urinalysis in a few days to determine if hematuria is transient or persistent.
Transient microscopic hematuria is a common problem in adults. One study evaluated 1000
young men who had yearly urinalyses between the ages of 18 and 33; hematuria was seen
in 39 percent on at least one occasion and 16 percent on two or more occasions [17].
Hematuria has also been found in up to 13 percent of postmenopausal women [4]. No
obvious etiology can be identified in most cases. Fever, infection, trauma, and exercise are
potential causes of transient hematuria. (See "Exercise-induced hematuria").
Malignancy risk in older patients with transient hematuria — An important
exception occurs in older patients in whom even transient hematuria carries an appreciable
risk of malignancy (assuming no evidence of glomerular bleeding) [2,5,18,19]. One report
studied 1034 patients with more than 5 red cells per high power field on at least 1 of 3
screening urinalyses. All patients were evaluated by ultrasonography, intravenous
pyelography (IVP), urinary cytology, and cystoscopy; the incidence of malignancy (bladder,
kidney, or prostate) was 2.4 percent. Neither cytology nor IVP reliably detected all of the
tumors. Ultrasonography was very accurate for renal tumors, while cystoscopy was required
to reliably diagnose bladder or prostatic cancers [5].
Tumors were more common in men and all but one occurred in patients over the age of 50.
Another 20 percent of patients had kidney stones or glomerular or other intrinsic renal
disease, while the remaining 78 percent had either no identifiable cause or a minor lesion
such as benign prostatic hypertrophy [5]. Other screening studies limited to healthy men
over the age of 50 to 60 found an even greater risk: 8 to 9 percent of patients with
intermittent asymptomatic hematuria, as detected by screening with a dipstick for heme,
had a urinary tract malignancy [18,19].
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An even greater concern about underlying malignancy applies to patients with persistent
hematuria in whom there is no obvious cause from the history and no clear evidence of
glomerular disease, such as red cell casts. In one study, the incidence of malignancy
(mostly arising from the bladder) ranged from 5 percent with microscopic hematuria to as
high as 20 percent with gross hematuria [13]. Another study of 1000 patients found an
overall incidence of malignancy of 8 percent; this proportion was clearly age-dependent,
increasing substantially in patients over age 50 [2].
RADIOLOGIC TESTS — Once glomerular bleeding has been excluded in a patient with
otherwise unexplained hematuria, the diagnostic work-up should include a search for lesions
in the kidney, collecting system, ureters, and bladder. The diagnostic yield in adults
increases with age and is higher for gross hematuria (5 to 23 percent) than for microscopic
hematuria (up to 14 percent) [20], and for higher grades of bleeding than for lesser grades.
The optimal radiologic evaluation for isolated hematuria is uncertain because the great
majority of patients will have negative or minor findings (show table 2) [17]. Nevertheless,
if there is no specific clue to the correct diagnosis (such as kidney stones or red cell casts),
most physicians will order an intravenous pyelogram (IVP) or a renal ultrasound, looking for
calculi, a renal mass, or polycystic kidney disease [3,5].
An IVP is a reasonable first choice in young patients, since it can detect lesions such as
medullary sponge kidney that may not be seen by ultrasonography. It is also preferred by
urologists in older patients because it can detect lesions in the renal pelvis and ureters. In
patients who have a contraindication to IVP (eg, dye allergy), ultrasound is the usual
alternative [21]. Some studies suggest that ultrasonography has a somewhat lower
diagnostic yield, while others found that it is more accurate [22].
Young patients with a normal IVP do not need ultrasonography, since the yield of significant
findings is very low [23]. However, older patients with a normal IVP should undergo
ultrasonography or helical CT scan, which are better at visualizing small renal tumors
[3,24].
URINE CYTOLOGY — A voided urine specimen should be sent for cytology in patients at
increased risk for urothelial cancers (see next section). The sensitivity of urine cytology is
greatest for carcinoma in situ of the bladder (approximately 90 percent). By comparison,
sensitivity for upper tract transitional cell carcinoma is limited, with the reported false
negative rate overall being 65 percent (and as high as 96 percent with low grade tumors)
[25,26]. Urine cytology is frequently obtained during cystoscopy, which is usually performed
in patients at risk for malignancy.
Among patients at low risk for genitourinary cancer (such as individuals under the age of 40
without specific risk factors), some investigators recommend that either urine cytology or
cystoscopy be performed [27]. Cystoscopy is subsequently done if malignant and/or
atypical/suspicious cells are identified.
INDICATIONS FOR CYSTOSCOPY — The indications for cystoscopy when the IVP,
ultrasonography, and/or CT scan and urine cytology are negative are incompletely defined
[27]. The yield of these procedures is very low in men under the age of 40 and in low-risk
women [3,14,20,28]. In general, cystoscopy is recommended in those patients at risk for
bladder cancer: men over the age of 50 [3,5,18,19]; and those with specific risk factors
such as prolonged heavy phenacetin use, heavy smoking, exposure to certain dyes, or longterm administration of cyclophosphamide[20,27,29]. Analgesic abusers also have an
increased incidence of carcinoma of the kidney. (See "Urinary tract malignancy and
atherosclerotic disease with chronic analgesic abuse").
There is a field cancerization effect for urothelial tumors. Thus, among patients with
hematuria who first undergo cystoscopy and are found to have a bladder tumor, the upper
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tracts should also be evaluated for possible lesions in the renal pelvis and ureter. (See
"Clinical presentation; diagnosis; and staging of bladder cancer").
Cystoscopy is also indicated in the infrequent patient with otherwise unexplained persistent
or intermittent gross hematuria. It may be possible with this procedure to determine if the
bleeding is originating from the bladder or from one or both ureters. Unilateral bleeding may
be due to an arteriovenous malformation, fistula, or venous varices (see below) [29].
UNEXPLAINED HEMATURIA — If no diagnosis is apparent from the history, urinalysis,
radiologic tests, or cystoscopy, then the most likely causes of persistent isolated hematuria
are a mild glomerulopathy as described above, or a predisposition to stone disease,
particularly in young and middle-aged patients [14,30].
Glomerular disease — Approximately 50 percent of patients with idiopathic hematuria
have a glomerular disease, which is more likely to persist than other causes of isolated
hematuria. In one study, 86 percent of patients with hematuria persisting for four years had
either IgA nephropathy or thin basement membrane disease [30].
Hypercalciuria and hyperuricosuria — As many as 30 to 35 percent of children with
apparently idiopathic hematuria (no proteinuria or infection, negative radiologic evaluation)
have hypercalciuria, while 5 to 20 percent of children with recurrent hematuria have
hyperuricosuria [31-33]; both disorders are often associated with a positive family history
(as high as 40 to 75 percent) of stone disease [31,33]. These children are at increased risk
for the future development of kidney stones. Lowering calcium excretion with a thiazide
diuretic typically leads to resolution of the hematuria among those with hypercalciuria [31];
a restricted purine diet or the administration of allopurinol commonly eliminates uricosuria
and hematuria in those with hyperuricosuria.
Similar findings may be present in adults. Some patients have hypercalciuria or
hyperuricosuria (as detected by a 24-hour urine collection) [34,35], while others have a
history suggestive of stone disease without these biochemical abnormalities (although
citrate excretion was not measured in this study) [30]. (See "Risk factors for idiopathic
calcium stones"). Treatment with a thiazide diuretic for hypercalciuria or allopurinol for
hyperuricosuria usually leads to disappearance of the hematuria [34].
Arteriovenous malformations and fistulas — Rare causes of hematuria include
arteriovenous malformations and fistulas, and the loin pain-hematuria syndrome. An
arteriovenous malformation (AVM) or fistula, either congenital or acquired, is an unusual
cause of hematuria. The primary presenting sign is gross hematuria, but high-output heart
failure and hypertension also may be seen [29]. The latter is presumably due to activation
of the renin-angiotensin system resulting from ischemia distal to the AVM [36]. The
diagnosis may be suspected if there is an irregular filling defect on intravenous pyelography
due to compression of the pelvis or calyx. The presence of an AVM can be confirmed by
arteriography (which demonstrates almost immediate visualization of the inferior vena
cava) or CT scanning. There are several therapeutic options. It is often possible for an
experienced radiologist to embolize the lesion at the time of arteriography by the injection
of absolute ethanol, steel coils, gelatin sponges, or balloons [37]. Absolute ethanol may be
safest; it denatures proteins in the vessel wall, leading to a coagulum that occludes the
lumen. Surgery or nephroscopy can be performed if embolization is ineffective or the
hematuria recurs [36,37].
Loin pain-hematuria syndrome — The loin pain-hematuria syndrome is a poorly defined
disorder characterized by loin or flank pain that is often severe and unrelenting and
hematuria with dysmorphic red cell features suggesting a glomerular origin [38,39]. Some
have suggested that these patients have a subtle disorder affecting the renal vasculature,
although this has not been a consistent finding. One report has suggested an important
psychologic component [40]. Fifteen patients with the clinical diagnosis of the loin painhematuria syndrome were compared with 10 patients with flank pain due to nephrolithiasis
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[40]. Patients in the former group were much more likely to have medically unexplained
somatic symptoms, an adverse psychologic event preceding the onset of pain, and a history
of greater analgesic ingestion. It was concluded that psychologic factors were of primary
importance in the loin pain; the origin of the hematuria was uncertain.
One possible explanation for the hematuria in some patients with the loin-pain hematuria
syndrome is thin basement membrane disease. (See "Thin basement membrane disease
(benign familial hematuria)"). One report found thin basement membrane disease in 7 of 15
patients in whom renal biopsy was performed for evaluation of possible loin pain-hematuria
syndrome [41]. It was proposed that bleeding into and obstruction of the renal tubules was
responsible for the loin pain. Four of these seven patients had a beneficial response to the
administration of an angiotensin converting enzyme inhibitor, possibly due to a reduction in
intraglomerular pressure. Whether this approach might be beneficial in other patients is not
known.
At present, optimal treatment of the loin pain-hematuria syndrome is unclear. The primary
goal is frequently pain relief. Various treatment modalities may be utilized, ranging from
nonsteroidal antiinflammatory drugs to nerve blocks to surgery. Dependence upon narcotics
can occur in patients with unrelenting and debilitating discomfort. Some investigators
advocate renal autotransplantation as definitive and effective therapy [42], while others
report only temporary relief from this procedure [43].
Follow-up studies — The most serious disorder in the patient with unexplained hematuria
is the presence of an undiagnosed carcinoma of the urinary tract. The combination of
negative radiologic examination(s) (which may include IVP, ultrasonography, and/or helical
CT scan alone or in combination), negative cytology, and negative cystoscopy is usually
sufficient to exclude malignancy in the urinary tract [5]. However, a malignancy will
subsequently become evident in some cases; as an example, approximately 1 percent of
older patients with an initially negative evaluation will, at three to four years, have a
detectable urinary tract malignancy [5].
As a result, initial and then periodic urine cytology and urinalyses should be performed in
patients at high risk for malignancy (at 6, 12, 24 and 36 months) [27]. Some physicians
also recommend repeat ultrasonography and cystoscopy at one year in high-risk patients
with persistent hematuria [3,5,13]. On the other hand, low-risk patients with persistent
idiopathic microscopic hematuria are usually followed with periodic urinalyses and urine
cytology.
SCREENING FOR HEMATURIA — Screening for hematuria in patients who have no
symptoms suggestive of urinary tract disease is not recommended. The most plausible
argument for screening would be for the early detection and treatment of cancers of the
kidney, collecting system, or bladder in older adults. However, these and other diseases
causing hematuria do not meet basic criteria for screening [44]: the prevalence of
undetected, asymptomatic, early disease is relatively low; and there is little evidence that
hematuria is a sensitive test for localized disease, or that (in the case of renal cancer) early
treatment of local disease results in a better prognosis. Thus, expert groups such as the
United States Preventive Services Task Force on the Periodic Health Examination do not
recommend screening for disease by tests for hematuria.
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