CLINICAL PRACTICE

Diagnostic algorithm for the evaluation of hematuria

Xinying Shen, MSN, CRNP, ACNP-BC, CCRN (Student)
Adult Acute Care Nurse Practitioner Program, University of Pennsylvania School of Nursing, Philadelphia, Pennsylvania

Keywords
Hematuria; diagnostic algorithm; blood in
urine.
Correspondence
Xinying Shen, MSN, CRNP, ACNP-BC, CCRN,
PHGI Associates, Ltd., 230 W. Washington
Square, Philadelphia, PA 19106.
Tel: 215-400-0357; Fax: 215-829-3561;
E-mail: xinyings@yahoo.com
Received: July 2008;
accepted: October 2008
doi:10.1111/j.1745-7599.2010.00491.x
Disclosures
The author reports no competing interests.
Abstract
Purpose: To present a logical and cost-effective diagnostic approach for
primary care physicians to a common symptom, hematuria.
Data source: Selected research, review articles, as well as medical textbooks
and current government guidelines.
Conclusion: Dipstick test and microscopic urinalysis are two common
screening tests for hematuria. Once hematuria is discovered, its etiology should
be investigated through a comprehensive history, a focused physical exami-
nation, laboratory studies, and radiographic imaging. Microscopic urinalysis
is simple yet important in distinguishing glomerular from nonglomerular
sources of bleeding. Intravenous urography, renal ultrasonography, or com-
puted tomography may be needed to determine the location and characteristics
of lesions. Cytoscopy is important in evaluating lower urinary tract lesions.
Implications for practice: Hematuria is a frequently encountered symptom
that has a broad differential diagnosis ranging from insignificant etiology
to potentially life-threatening neoplastic lesions. A systematic method can
be useful in efficiently and cost-effectively managing hematuria. Early and
appropriate diagnosis of this common symptom results in improved clinical
outcomes.

Hematuria is a common clinical problem, with an overall
prevalence of 1%–16% in adults, depending on the
criteria used to define hematuria, the population studied,
and the type of test that the diagnosis was based on (Hiatt
& Ordonez, 1994; Mariani et al., 1989; Woolhandler,
Pels, Bor, Himmelstein, & Lawrence, 1989). The usual
definition of hematuria is the presence of more than two
to three red blood cells (RBCs) per high-power field (hpf)
in a centrifuged urine specimen (Cohen & Brown, 2003;
Sutton, 1990; Yun, Meng, & Carroll, 2004). In many
people, it can be transient or of no consequence. For
example, healthy people can excrete as many as three
RBCs per hpf, or even more after strenuous exercise
because of injuries to structures in the genitourinary
tract. However, for some people, especially older adults,
hematuria can be a sign of significant genitourinary
disease, such as renal or urinary malignancies. However,
because hematuria associated with significant disease may
be intermittent in nature, it is suggested that patients
with more than three RBCs per hpf on two of three urine
specimens should undergo evaluation (Mariani et al.).
Urine dipstick is currently the simplest and most com-
mon test used in clinical practice and has been shown
to be 91%–100% sensitive and 65%–99% specific for
detecting more than three RBCs per hpf (Woolhandler
et al., 1989). However, a false-positive result can happen
in the presence of myoglobin, hemoglobin, and oxidizing
agents, such as povidone-iodine and hypochlorite (Yun
et al., 2004). The test may also be positive during dehy-
dration because of the elevation of urine specific gravity.
Microscopic examination of the urinary sediment
(urinalysis) is the gold standard test. It not only detects
the presence of RBCs, but also the morphologic features
of RBCs, the presence of white blood cells (WBCs), casts,
or crystals, hence it is helpful in distinguishing glomerular
and nonglomerular causes of hematuria.

186 Journal of the American Academy of Nurse Practitioners 22 (2010) 186–191 © 2010 The Author
Journal compilation © 2010 American Academy of Nurse Practitioners
X. Shen Diagnostic algorithm for hematuria

Differential diagnosis
Hematuria can be a sign of a life-threatening disease,
such as bladder or renal cancer, or it can be a sign of a
progressive but benign disease, such as benign prostatic
hyperplasia (BPH); it can be the harbinger of a systemic
disease, or it can even be factitious. Table 1 summarizes
the differential diagnosis for gross or microscopic
hematuria. In a retrospective analysis (Carter & Rous,
1981) of 110 patients who presented with hematuria, the
most common cause was neoplasma (41.8%), the second
most common etiology was infection (26%), followed by
BPH (19%) and nephrolithiasis (13.6%).
Diagnostic approach
Patient history and physical examination
The workup for hematuria should start with a com-
prehensive health history and physical examination. A
thorough health history will include medical and sur-
gical history, family history, social history, occupational
or radiation exposure, all medications taken, as well as
ingestion of certain foods. (An algorithm depicting the
complete diagnostic approach is available as online sup-
porting information Figure S1.)
Increased frequency and dysuria may suggest urinary
tract infection. Colicky pain suggests nephrolithiasis. A
recent sore throat (e.g., pharyngitis) or skin infection
(e.g., impetigo) may suggest possible poststreptococcal
glomerulonephritis. If menstruation, vigorous exercise,
or sexual activities are suspected as the possible etiology,
repeat urinalysis can be obtained.
Grossly visible red to brown color does not necessarily
indicate blood in urine. A lot of medications or substances
(Table 2) can lead to discoloration of urine, such as beets
or phenazopyridine, and can turn the urine brown or

Table 1 Differential diagnosis of hematuria

Etiology of hematuria

Glomerular origin Extrarenal tumors

IgA nephropathy (Berger’s disease) Bladder cancer
Thin basement membrane disease Prostate cancer
Hereditary nephritis (Alport syndrome) Renal pelvis, ureter, urethra tumors
Poststreptococcal glomerulonephritis Benign bladder or ureteral polyps
Mesangial proliferative glomerulonephritis Lower urinary tract
Focal glomerular sclerosis Benign prostatic hyperplasia
Rapidly progressing glomerulonephritis Stones or foreign body
Lupus nephritis Interstitial cystitis
Fabry disease Radiation-induced cystitis
Tubulointerstitial disease Bladder diverticulum
Papillary necrosis Bladder papilloma
Interstitial nephritis Urethral and meatal stricture
Analgesic nephropathy Systemic or other diseases
Nephrolithiasis Bleeding diathesis (e.g., hemophilia)
Reflux nephropathy Sickle cell disease
Hydronephrosis Abdominal aortic aneurysm
Ureteropelvic junction obstruction Lymphoma
Renal tumors Multiple myeloma
Familial condition Infectious causes
Polycystic kidney disease Pyelonephritis, cystitis, prostatitis, urethritis, epididymitis
Medullary sponge kidney Tuberculosis
Renal vascular causes Urinary schistosomiasis
Renal arteriovenous malformation Cytomegalovirus infection
Renal vein thrombosis Infectious mononucleosis
Renal Infarction Condyloma acuminatum
Malignant hypertension Genitourinary trauma
Vasculitis (Henoch–Schönlein purpura, periarteritis nodosa, Indwelling catheters
Wegener granulomatosis) Strenuous exercise
Metabolic Medications or drugs (see Table 3)
Hypercalciuria Excessive aticoagulants
Hyperuricosuria Chemotherapy drugs leading to hemorrhagic cystitis
Analgesics leading to analgesic nephropathy

Note. Information from Massry and Glassock (2001).

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Diagnostic algorithm for hematuria X. Shen

Table 2 Causes of discoloration of urine Table 3 Drugs that can cause hematuria

Substances or medications that can cause discoloration of urine Drugs Renal adverse effects

Foods Beets; blackberries; paprika; rhubarb Captopril (Capoten) Interstitial nephritis

Laxatives Cascara; phenolphthalein; senna Nonsteroidal antiinflammatory
Antibiotics Nitrofurantoin; rifampin; sulfonamides drugs (NSAIDs)
Anticonvulsants Phenytoin Olsalazine (Dipentum)
Antimalarials Chloroquine; plaquenil Omeprazole (Prilosec)
Antiparkinsonian Levodopa Diuretics
Genitourinary agents Pyridium Furosemide (Lasix)
Vitamins Riboflavin Chlorothiazide (Diuril)
Anticancer agents Doxorubicin; daunorubicin Ethacrynic acid
Tranquilizer Phenothiazine Antimicrobials
Immunosuppressants Azathioprine Penicillins
Others Bilirubin; melanin; porphyrins; Polymycin
deferoxamine (an iron chelating agent) Cephalosporins
Ciprofloxacin (Cipro)
Note. Information from Massry & Glassock (2001); Restrepo & Carey Rifampin (Rifadin)
(1989). Silver sulfadiazine (Silvadene)
Trimethoprim-sulfamethoxazole
(Bactrim)
Analgesics Papillary necrosis
NSAIDs, aspirin
orange. These causes of discoloration of urine can be Cyclophosphamide (Cytoxan) Hemorrhagic cystitis
Mitotane (Lysodren)
further confirmed by a negative urine dipstick test.
Ifosfamide (Ifex)
Eliciting a family history of polycystic kidney disease, Oral contraceptives Renal vein thrombosis, loin-pain
sickle cell anemia, or other renal disease, and inquiring hematuria syndrome
about travel history to schistosomiasis, malaria, or Carbonic anhydrase inhibitors Urolithiasis
tuberculosis endemic area can also give some clue about Dichlorphenamide (Daranide)
Indinavir (Crixivan)
the etiology. Black or African-American descent patients
Mirtazapine (Remeron)
should be screened for sickle cell traits or disease, which Ritonavir (Norvir)
can lead to papillary necrosis and hematuria. Several Triamterene (Dyrenium)
medication classes can cause hematuria (see Table 3)
Note. Information from Restrepo & Carey (1989); Spector (2003).
(Mazhari & Kimmel, 2002; Restrepo & Carey, 1989;
Thaller & Wang, 1999). Chemotherapy agents such as Table 4 Possible physical examination findings of hematuria
cyclophosphamide and mitotane can induce hemorrhagic
cystitis. Penicillin and cephalosporin may lead to allergic Physical examination findings Possible causes of hematuria

interstitial nephritis. Heavy or surreptitious use of Peripheral edema Nephrotic syndrome

analgesics can be associated with analgesic nephropathy Petechiae or mottling Coagulopathy
and papillary necrosis. Chronic use of nonsteroidal Cardiac dysrrhythmia, such as Renal artery embolism
atrial fibrillation
antiinflammatory drugs, especially phenacetin, has been
Costovertebral angle tenderness Pyelonephritis or nephrolithiasis
implicated in malignant transformation of the urothelium Hypertension Nephrosclerosis
(Gonwa, Corbett, Schey, & Buckalew, 1980). Abdominal bruit Abdomial aortic aneurysm
Physical exam (Table 4) should incorporate examina- Enlarged prostate BPH or urinary tract infection
tion of systems related to potential etiology of hematuria.
Evaluate the extremities for peripheral edema, petechiae,
Laboratory studies
or mottling. Evaluate hearing if Alport syndrome is
suspected. Examine the cardiovascular system for hyper- Because of the simplicity of the test, urine dipstick
tension, heart murmur, or irregular heart rhythm. Dysr- can be the first laboratory test performed to provide
rhythmias, such as atrial fibrillation, predispose patients a semiquantitative measurement of RBCs, WBCs, and
to renal artery embolism. Evaluate the abdomen for protein. However, it can give false-positive results;
organomegaly, costovertebral angle tenderness, or flank therefore, a positive dipstick test must always be
mass. Examination of the prostate, genital, urethral mea- confirmed with microscopic urinalysis.
tus, and rectum can provide evidence of BPH, prostatitis, If the urine looks grossly discolored, but the urine dip-
prostate cancer, epididymitis, or meatal stenosis. stick test is negative, discoloration of urine by medications

188
X. Shen
or other substances (Table 2) should be considered. If the
urine dipstick test is positive, but no RBCs are seen under
microscopic urinalysis, hemoglobinuria, or myoglobinuria
should be evaluated.
Microscopic urinalysis can determine not only the
quantitative measurement of RBCs and WBCs but also
the morphology of RBCs and the presence of casts and
crystals, hence giving a clue of the origin of hematuria.
The presence of dysmorphic RBCs (irregular outer cell
membrane of RBCs), RBC casts, or proteinuria supports a
diagnosis of hematuria of glomerular origin.
The presence of RBC casts, a finding that is specific,
but not sensitive, usually suggests a glomerular cause of
hematuria. If RBC casts are not present, RBC morphology
can be examined. Dysmorphic RBCs usually suggest
glomerular origin of hematuria, especially acanthocytes
(ring-formed erythrocytes with membrane protrusions or
blebs of variable size and shape), which are usually more
strongly associated with glomerular etiology (Cohen &
Brown, 2003). The uniform, biconcave disk shape of
normal erythrocytes, classified as isomorphic, usually
suggests lower urinary tract (nonglomerular) bleeding.
Clumped erythrocytes (microscopic clots) usually suggest
lower urinary tract bleeding (Thaller & Wang, 1999).
If proteinuria is detected on a dipstick test, a random or
24-h quantitative measurement can be done. Proteinuria
>500 mg/24 h or urinary protein concentration to urine
creatinine ratio >0.3 on random specimen is typically
associated with glomerular disease. Renal function should
also be evaluated. If clinically significant proteinuria
or elevated serum creatinine is present, the patient
should be referred to a nephrologist, and renal biopsy
may be warranted to distinguish different types of
glomerulonephritis, predict prognosis, and guide therapy.
IgA nephropathy, thin basement membrane disease, and
Alport syndrome (hereditary nephritis) are the three
most prevalent glomerular causes of isolated hematuria.
Although their clinical courses are benign, and usually
not associated with progressive loss of renal function,
many other forms of glomerulonephritis have an ominous
prognosis (Mazhari & Kimmel, 2002; Yun et al., 2004).
If either bacteriuria or pyuria is present, urine Gram
stain or culture with sensitivity should be performed.
Other screening studies include testing for bleeding
diathesis (e.g., complete blood count, platelet count,
prothrombin time, and partial thromboplastin time),
serum chemistries (e.g., serum calcium, uric acid, blood
urea nitrogen [BUN], creatinine) for metabolic or other
systemic causes of hematuria, and serologic studies (e.g.,
titers of antistreptolysin O, serum complement levels)
for glomerulonephritis. If the patient is Black or of
African-American descent, sickle cell trait should be
tested. A special consideration is that oral anticoagulation
Diagnostic algorithm for hematuria
alone does not cause hematuria, except in the case
of marked overdose of coumadin; therefore, patients
on anticoagulation presenting with hematuria should
undergo prompt investigation.
Radiographic imaging studies of upper
urinary tract
If a glomerular cause of hematuria is excluded, the
next step in the diagnostic workup is to search for
lesions in the kidney, collecting system, ureters, bladder,
and urethra. The available radiographic imaging studies
of upper urinary tract include intravenous urography
(IVU), retrograde pyelography, ultrasonography (US),
conventional computed tomography (CT), CT urography,
and magnetic resonance imaging (MRI).
IVU or excretory urography is conventionally the initial
radiographic study. It can provide detailed and excellent
anatomical images of the collecting system, specifically
the pelvicalyceal system, and filling defects within the
ureter. It is relatively inexpensive, but it is not suitable
for evaluating the bladder and urethra. It also requires
contrast media, which poses a risk of nephrotoxicity in
patients with renal insufficiency. US is safer (without
exposing patients to contrast media) and has alternatively
been used as the initial imaging study. It is excellent
for detecting a renal cyst or parenchymal mass, but not
as good as IVU in delineating the collecting system and
ureter. Both IVU and US have low sensitivity in detecting
solid masses smaller than 3 cm.
CT with contrast is as good as the MRI. It is the best
imaging study for detecting small renal parenchymal
masses and renal abscesses (Grossfeld et al, 2001b;
Mazhari & Kimmel, 2002; Yun et al., 2004). Most often,
a noncontrast CT is performed first for suspected stone
disease. CT with contrast can be the next step because it
excellently identifies the characteristics of kidney masses.
For patients who cannot tolerate contrast media but have
high risk for urologic malignancy, the combination of
US and retrograde pyelography (retrograde filling of the
ureters with contrast) can be the alternative to IVU and
CT. MRI also provides excellent images of upper urinary
tract, but because of the cost and limited availability it
rarely is used as the initial test.
Recently, CT urography started to replace IVU or US
as the initial imaging study in many centers because
it combines the benefits of conventional CT (with and
without contrast) and IVU. During CT urography, images
of the urinary tract are obtained first without contrast,
and then intravenous contrast media are administered
to evaluate the renal parenchyma. The next step is the
pyelographic phase when the urothelium is evaluated.
Hence, CT urography can picture the whole upper
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Diagnostic algorithm for hematuria
urinary tract including both the renal parenchyma and
urothelium. The major concern of CT urography currently
is radiocontrast exposure, which is significantly higher
than IVU and limits its wide use.
Evaluation of lower urinary tract
If the etiology of hematuria is still obscure after
investigation of evidence of glomerular hematuria and
imaging of the upper urinary tract, evaluation of the
lower urinary tract is necessary. Cytologic examination
of exfoliated cells within the urine is currently a
noninvasive and cost-effective test for detecting urothelial
malignancy. It has a sensitivity of 40%–76%, depending
on the stage of malignancy and the expertise of the
cytopathologist. Sensitivity is higher if the specimen
tested is obtained from the first void in the morning on
three consecutive days or the barbotaged specimen during
cytoscopy (Badalament et al., 1987). This test has a high
specificity; hence, positive urinary cytologies are almost
diagnostic of urothelial malignancy (Yun et al., 2004). The
American Urological Association recommends that for
those who refuse cytoscopy or are considered at low risk
for malignancy, voiding urine cytologic testing alone can
be done (Grossfeld et al., 2001b). Patients at high risk for
uroepithelial tumors (Table 5) should undergo complete
evaluation with cystoscopic examination of the bladder.
During the procedure, urethra, prostate, bladder mucosa,
and ureteral orifices can be directly visualized, and a
bladder wash (barbotaged specimen) can be obtained for
cytologic examination of malignancy.
Summary
Hematuira can be a sign of serious underlying genitouri-
nary disease. Although routine screening of hematuria
with urine dispstick is currently not recommended, once
hematuria is detected its causes need to be investigated.
Table 5 Risk factors for uroepithelial malignancy
Risk factors for uroepithelial malignancy
Cigarette smoking
Age >40 years old
Occupational exposures (chemicals or dyes)
Dietary nitrites and nitrates
Overuse analgesics (e.g., phenacetin)
Urinary schistosomiasis
Past treatment with high dose of cyclophosphamide (Cytoxan)
Ingestion of aristolochic acid found in some herbal weight-loss
preparations
Pelvic irradiation
People with irritative voiding
190
X. Shen
A systematic method is useful in efficiently and cost-
effectively evaluating hematuria. Hence, based on the
literature and the American Urological Association Best
Practice Policy (Grossfeld et al., 2001a,b), a diagnostic
algorithm is presented to help the clinicians effectively
manage hematuria (Figure S1). Early and appropriately
diagnosing the etiology of hematuria by the practitioner
can result in appropriate referral to the nephrologists or
urologists, thus ensuring optimal treatment decisions and
better outcome.
Acknowledgments
The author would like to acknowledge the thoughtful
and helpful review of this article by Ylenia Quiaiot,
MSN, CRNP.
Supporting Information
Additional supporting information may be found in the
online version of this article:
Figure S1 Diagnostic algorithm for the evaluation of
hematuria.
Modified from Cohen, R. A., & Brown, R. S. (2003).
Clinical practice. Microscopic hematuria. New England
Journal of Medicine, 348, 2330–2338, and Yun, E.J., Meng,
M.V., & Carroll, P.R. (2004). Evaluation of the patient
with hematuria. Medical Clinics of North America, 88,
329–343.
Please note: Wiley-Blackwell is not responsible for the
content or functionality of any supporting materials
supplied by the authors. Any queries (other than missing
material) should be directed to the corresponding author
for the article.
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