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Official reprint from UpToDate® www.uptodate.com

©2013 UpToDate®

Evaluation of gross hematuria in children

Author Section Editors Deputy Editor

Marie France Gagnadoux, MD Patrick Niaudet, MD Melanie S Kim, MD
Laurence S Baskin, MD, FAAP

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2013. | This topic last updated: mar 28, 2012.

INTRODUCTION — Gross hematuria is defined by the presence of an increased number of red blood cells (RBCs)
in the urine that is visible to the naked eye. Although an uncommon occurrence in children, nevertheless it is a
disturbing finding for both the affected child and his/her family.

The causes and evaluation of gross hematuria in children will be reviewed here. The evaluation of children with
microscopic hematuria is discussed separately. (See "Evaluation of microscopic hematuria in children".)

DETECTION — Gross hematuria is suspected when red or brown urine is present. However, red or brown urine can
be due to causes other than blood including the following (table 1):

Pigments from drugs (eg, phenazopyridine) or foods (eg, beets)

Metabolites associated with other clinical conditions (eg, porphyria)
Free hemoglobin or myoglobin

Thus, the initial step in the evaluation of patients with red urine is to establish whether or not the urine discoloration
is due to blood or another substance. This is accomplished by the following two procedures:

Urinary dipstick test for blood — The reagent strip that detects blood utilizes hydrogen peroxide, which
catalyzes a chemical reaction between hemoglobin (or myoglobin) and the chromogen tetramethylbenzidine.
If the urinary dipstick test is positive for blood, the likely cause of the red/brown pigmentation is blood, or free
hemoglobin or myoglobin. A negative test eliminates these etiologies as the cause of urinary discoloration.

Urine centrifugation — If after centrifugation of the urine specimen, the sediment is red/brown then the
etiology is most likely blood (algorithm 1). If the supernatant is red/brown and the sediment is not discolored,
than the red/brown urine is not due to blood but to another substance, such as free hemoglobin or
myoglobin. Microscopic examination of the sediment should confirm the presence of red blood cells. (See
"Urinalysis in the diagnosis of kidney disease", section on 'Red to brown urine'.)

In patients with gross hematuria, 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.

ETIOLOGY — The most commonly identified etiologies for gross hematuria in children include urinary tract
infection (UTI), irritation of the meatus or perineum, and trauma [1,2]. Other less common causes include
nephrolithiasis, sickle cell disease/trait, coagulopathy, glomerular disease including postinfectious
glomerulonephritis and IgA nephropathy, malignancies (eg, Wilms' tumor and rarely transitional cell carcinoma of
the bladder), and drug-induced hemorrhagic cystitis, such as seen with cyclophosphamide [1].

The relative frequency of the known causes of gross hematuria in children varies depending upon the clinical
setting. This is illustrated by several case series of children with gross hematuria who presented to three different
clinical settings (ie, a pediatric emergency room [1], a pediatric urology referral service [3], or a pediatric nephrology
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referral service [4]).

In a 1977 two-year retrospective review of 150 patients presenting to a tertiary pediatric emergency center with
gross hematuria, either documented (n=39) or suspected (n=35) urinary tract infection (UTI) was the underlying
diagnosis in half of the patients [1]. Other causes included perineal or urethral irritation (18 percent), trauma (7
percent), acute nephritis (4 percent), coagulopathy (3 percent), and stone (2 percent). In 10 percent of patients, no
etiology was found.

In a 10-year retrospective review of 342 children who presented with gross hematuria to a pediatric urologic center in
the United States between 1994 and 2004 [3], the causes of gross hematuria and their frequency included urethral
irritation or trauma (15 percent), urinary tract infection (14 percent), underlying congenital anomalies, such as
vesicoureteral reflux (VUR), posterior urethral valves, or ureteropelvic junction obstruction, (13 percent),
nephrolithiasis (5 percent), and malignancy (1 percent). In 35 percent of the patients, no cause could be
determined. In addition, bladder or urethral abnormalities were seen in 76 of 136 patients who underwent
cystoscopy including posterior urethritis (n=25), cystitis (n=25), bladder trabeculation (n=7), and urethral stricture
(n=6).

In this urologic case series, there were no cases of glomeruli disease, which is most likely due to referral bias. This
was illustrated by the third retrospective case series from a pediatric nephrology referral center that demonstrated a
greater proportion of cases due to glomerular disease compared to both of the two previous studies [4]. In this
review, results were based upon 82 of 100 patients with completed evaluation. The following findings were noted:

A glomerular cause was identified in 24 patients (29 percent). The two most common diagnoses were IgA
nephropathy (n=13) and Alport syndrome (n=6). (See "Clinical presentation and diagnosis of IgA
nephropathy" and "Genetics, pathogenesis, and pathology of hereditary nephritis (Alport syndrome)".)

Nonglomerular etiology was established in 30 patients (37 percent). The most common diagnoses were
hypercalciuria (n=9), urethral irritation or trauma (n=8), and hemorrhagic cystitis (n=7).

No cause was found in the remaining 28 patients (34 percent). In 26 of these patients, the hematuria was
attributed to a nonglomerular source.

In the two referral based studies, boys were at a higher risk for gross hematuria than girls because of their
increased susceptibility to trauma of the urethral meatus [3,4]. However, in the first study, there was no gender
difference. The increased prevalence of female patients with gross hematuria due to urinary tract infections seen in
the emergency room setting appears to have offset the predominance of boys with recurrent gross hematuria due to
trauma resulting in the reported equal distribution of boys and girls [1].

EVALUATION — The majority of children who present with gross hematuria have an easily recognizable and
apparent cause [1]. The clinician generally is able to establish the underlying etiology by a complete history,
physical examination, and urinalysis (algorithm 2).

Historical clues — There are often clues from the history that point toward a specific diagnosis.

Recent vigorous exercise or trauma. (See "Exercise-induced hematuria".)

History of new onset of incontinence, dysuria, frequency, or urgency, suggests UTI as a possible cause.
(See "Clinical features and diagnosis of urinary tract infections in infants and children older than one month",
section on 'Clinical presentation'.)

History of unilateral flank pain that may radiate to the groin suggests obstruction caused by a calculus or
blood clot. In comparison, flank pain without radiation but with fever, dysuria, and frequency and/or urgency
is suggestive of acute pyelonephritis. (See "Clinical features and diagnosis of urinary tract infections in
infants and children older than one month", section on 'Clinical presentation'.)

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The timing of hematuria during micturition, especially terminal hematuria, suggests urethral bleeding.

The color of urine may distinguish glomerular bleeding from extraglomerular bleeding. Glomerulonephritis is
associated with brown urine. Bleeding from the lower urinary tract is suggested by pink or red urine and may
be accompanied by blood clots. (See "Etiology and evaluation of hematuria in adults", section on
'Glomerular versus nonglomerular bleeding' and 'Urinalysis' below.)

A history of pharyngitis or impetigo (two or three weeks prior to onset of hematuria) suggests
poststreptococcal glomerulonephritis, although a recent upper respiratory (one or two days prior to onset of
hematuria) infection can be associated with IgA nephropathy. (See "Differential diagnosis and evaluation of
glomerular disease", section on 'Hematuria following upper respiratory infection'.)

A history of predisposing clinical conditions such as sickle cell disease or trait [5] or coagulopathy such as
severe hemophilia.

Exposure to medications that can cause hemorrhagic cystitis (such as cyclophosphamide), or nephritis
(although hematuria is not typically the central manifestation in such patients). (See "Clinical manifestations
and diagnosis of acute interstitial nephritis", section on 'Drugs'.)

Physical examination — The physical examination should include measurement of blood pressure, assessment
for edema and recent weight gain, close skin examination (eg, purpura), direct visualization of the genitals (looking
for penile urethral meatal erosion or female introitus pathology), and evaluation for abdominal discomfort or masses
(eg, Wilms' tumor).

Urinalysis — Examination of the urine may suggest an underlying etiology and potential site of bleeding
(glomerular versus extraglomerular).

Glomerular bleeding — Signs of glomerular bleeding include red cell casts (pathognomonic for glomerular
disease) (picture 1); red cells having a dysmorphic appearance; and brown, cola-colored urine (table 2). In a
first morning urinary sample, protein excretion greater than 100 mg/m2 at a time when there is no gross
bleeding is also indicative of glomerular source of blood. Although helpful if present, the absence of these
findings does not exclude glomerular disease.

Morphologic study of urinary RBCs, particularly with a phase-contrast microscope, may be helpful in distinguishing
glomerular from nonglomerular bleeding. The presence of more than 30 percent dysmorphic RBCs or of more than 5
percent of a specific form named an "acanthocyte" is highly suggestive of glomerular hematuria (picture 2A-B).
However, confident identification of such cells requires expertise in urinalysis. (See "Etiology and evaluation of
hematuria in adults", section on 'Glomerular versus nonglomerular bleeding'.)

Nonglomerular bleeding — In nonglomerular hematuria, the urine is typically red or pink in color. Microscopic
examination demonstrates urinary RBCs with a uniform normal size and shape (picture 3). Blood clots
virtually never occur with glomerular disease and are indicative of an extraglomerular source of hematuria.

The procedures for obtaining and processing urine samples in children are reviewed separately. (See "Urine
collection techniques in children".)

Further evaluation

Symptomatic hematuria — In patients who have symptomatic hematuria, further evaluation is guided by their
clinical symptoms, history, physical examination, and urinalysis (algorithm 2).

Trauma history — Obtain a CT scan of the abdomen and pelvis to determine the source of blood.

Signs or symptoms of UTI — Additional findings on urinalysis suggestive of a UTI include positive dipstick
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tests for leukocyte esterase and/or nitrite, more than five white blood cells per high-power field (spun urine),
and the presence of bacteria on a Gram stain of unspun urine.

An appropriately collected urine culture is obtained. If the culture is positive, treat appropriately and repeat
urinalysis after the infection has cleared.

Adenovirus should be considered as a potential etiology if urinary symptoms and urinalysis are suggestive of
infection but the culture is negative [6,7].

Signs or symptoms of perineal/meatal irritation — Supportive care and reassurance.

Signs or symptoms of nephrolithiasis — The evaluation begins with imaging. Renal ultrasonography is the
preferred modality in children. Abdominal plain films may be useful in identification of radiopaque stones but
will miss radiolucent uric acid stones, small stones or stones overlying bony structures, and will not detect
obstruction.

Spiral CT scan is the most sensitive imaging modality. However, because of concerns related to radiation exposure,
it is not typically the initial test in young children as it is in adolescents and adults. Consultation with radiology may
be warranted in younger children to determine the risk-to-benefit ratio of the test. (See "Diagnosis and acute
management of suspected nephrolithiasis in adults".)

Signs or symptoms suggestive of glomerular disease — Manifestations such as proteinuria, red blood cell
casts, edema, and hypertension suggest a glomerular source for the hematuria. The evaluation includes
serum creatinine, complete blood count, C3, C4, and serum albumin. Other tests to consider based upon
the history and the physical examination include ASO titer and/or streptozyme testing to detect
poststreptococcal glomerulonephritis, and antinuclear antibody testing to detect lupus nephritis. Such
patients should be referred to a pediatric nephrologist (or a clinician with expertise in the care of children with
renal disease).

Asymptomatic hematuria — Thorough diagnostic evaluation of children with asymptomatic gross hematuria is
often warranted and generally leads to a diagnosis. This was illustrated in a retrospective review of 228 patients who
presented to a single center for evaluation of asymptomatic gross hematuria [8]. Evaluation included complete
blood count, urinalysis, serum creatinine, serum C3, ultrasonography or intravenous pyelography, and renal biopsy
in some cases. Etiologies for gross hematuria included the following:

No identifiable cause — 36 percent

Hypercalciuria — 22 percent
IgA nephropathy —16 percent
Post-streptococcal glomerulonephritis — 7 percent
Other glomerulopathies including thin basement membrane disease — 2 percent
Congenital anomalies (eg, ureteropelvic junction obstruction or renal dysplasia) — 2 percent
Sickle cell trait — 1 percent

In addition, left renal vein compression between the aorta and proximal superior mesenteric artery, referred to as
"nutcracker syndrome," has been suggested as a cause of hematuria in children that is usually asymptomatic but
may be associated with left flank pain [9,10]. Nutcracker syndrome is detected by Doppler ultrasonographic
assessment of left renal vein diameter and peak velocity [9,11].

The frequency of hematuria due to nutcracker syndrome in children appears to be highest in Asia, with the
diagnosis rarely entertained in North America. This was illustrated in a Japanese case series of 85 children with
hematuria without nephritis, nephrolithiasis, or tumor. Doppler ultrasonographic findings were consistent with a
diagnosis of nutcracker syndrome in 21 of 23 children with gross hematuria and 17 of 52 patients with microscopic
hematuria [9]. Similar findings were noted in a report from Korea of 216 children with isolated microscopic or gross

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hematuria [10]. Doppler ultrasonographic results were consistent with nutcracker syndrome in 33 percent.

Nutcracker syndrome can also cause orthostatic proteinuria in children. (See "Orthostatic (postural) proteinuria",
section on 'Left renal vein entrapment'.)

In children with asymptomatic gross hematuria, we suggest using the following evaluation:

Urinalysis

Measurement of serum creatinine and C3

Urine culture

Measurement of urine calcium/creatinine to detect possible hypercalciuria, defined as a urine

calcium/creatinine ratio >0.2 (mg/mg)

Testing parents and siblings for hematuria (possible thin basement membrane disease or hereditary
nephritis)

Consider renal and bladder ultrasound with Doppler study to detect congenital abnormalities of the kidney or
urinary tract (CAKUT), tumor, or nutcracker syndrome. (See "Overview of congenital anomalies of the kidney
and urinary tract (CAKUT)".)

If there is a consideration of sickle cell trait or disease, a hemoglobin electrophoresis should be obtained.
(See "Renal manifestations of sickle cell disease".)

If no diagnosis is made and hematuria persists, the patient should be referred to a pediatric nephrologist or a
clinician with expertise in the care of children with renal disease. Patient referral is also recommended if there is
evidence of significant renal disease (ie, hypertension, elevated serum creatinine level, proteinuria, or evidence of
glomerular bleeding, such as red cell casts).

Cystoscopy — Cystoscopy is rarely indicated for hematuria in children. It should be reserved for the rare child with
a bladder mass noted on ultrasound and those with urethral abnormalities due to trauma.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and
“Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the
10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with
some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
“patient info” and the keyword(s) of interest.)

Basics topic (see "Patient information: Blood in the urine (hematuria) in children (The Basics)")

Beyond the Basics topic (See "Patient information: Blood in the urine (hematuria) in children (Beyond the
Basics)".)

SUMMARY AND RECOMMENDATIONS — Although gross hematuria is an uncommon occurrence in children,

nevertheless it is a disturbing finding for both the affected child and his/her family.

Gross hematuria is suspected when red or brown urine is present. However, red or brown urine may be due

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to causes other than blood, such as free hemoglobin or myoglobin, pigments from drugs (eg,
phenazopyridine) or foods (eg, beets), or metabolites associated with other clinical conditions (eg,
porphyria). (See "Urinalysis in the diagnosis of kidney disease", section on 'Red to brown urine'.)

Gross hematuria is distinguished from other causes of red/brown urine by the a positive urinary dipstick for
blood and a red/brown urine sediment. (See 'Detection' above.)

In children, urinary tract infection, irritation to the meatus or perineum, and trauma are the most common
causes of gross hematuria [1,2]. Other less common causes include nephrolithiasis, sickle cell
disease/trait, coagulopathy, glomerular disease including postinfectious glomerulonephritis and IgA
nephropathy, malignancies (eg, Wilms' tumor), and drug-induced hemorrhagic cystitis (eg,
cyclophosphamide). The reported relative frequency of these causes is dependent upon the clinical setting.
(See 'Etiology' above.)

The majority of symptomatic children who present with gross hematuria have an easily recognizable and
apparent cause generally detected by an initial evaluation that includes a complete history, physical
examination, and urinalysis (algorithm 2). Further testing is guided by the clinical findings of the initial
evaluation. (See 'Symptomatic hematuria' above.)

Diagnostic evaluation of asymptomatic patients usually determines an underlying cause of hematuria and
includes urinalysis, urine culture, testing family members for hematuria, ultrasonography of the kidneys and
bladder, and measurements of serum creatinine, serum C3 and urine calcium/creatinine. (See
'Asymptomatic hematuria' above.)

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REFERENCES

1. Ingelfinger JR, Davis AE, Grupe WE. Frequency and etiology of gross hematuria in a general pediatric
setting. Pediatrics 1977; 59:557.
2. Patel HP, Bissler JJ. Hematuria in children. Pediatr Clin North Am 2001; 48:1519.
3. Greenfield SP, Williot P, Kaplan D. Gross hematuria in children: a ten-year review. Urology 2007; 69:166.
4. Youn T, Trachtman H, Gauthier B. Clinical spectrum of gross hematuria in pediatric patients. Clin Pediatr
(Phila) 2006; 45:135.
5. Pham PT, Pham PC, Wilkinson AH, Lew SQ. Renal abnormalities in sickle cell disease. Kidney Int 2000;
57:1.
6. Badenas C, Praga M, Tazón B, et al. Mutations in theCOL4A4 and COL4A3 genes cause familial benign
hematuria. J Am Soc Nephrol 2002; 13:1248.
7. Buzza M, Wilson D, Savige J. Segregation of hematuria in thin basement membrane disease with haplotypes
at the loci for Alport syndrome. Kidney Int 2001; 59:1670.
8. Bergstein J, Leiser J, Andreoli S. The clinical significance of asymptomatic gross and microscopic hematuria
in children. Arch Pediatr Adolesc Med 2005; 159:353.
9. Okada M, Tsuzuki K, Ito S. Diagnosis of the nutcracker phenomenon using two-dimensional ultrasonography.
Clin Nephrol 1998; 49:35.
10. Shin JI, Park JM, Lee JS, Kim MJ. Effect of renal Doppler ultrasound on the detection of nutcracker syndrome
in children with hematuria. Eur J Pediatr 2007; 166:399.
11. Kim SH, Cho SW, Kim HD, et al. Nutcracker syndrome: diagnosis with Doppler US. Radiology 1996; 198:93.

Topic 6108 Version 13.0

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GRAPHICS

Causes of heme-negative red urine

Medications
Doxorubicin

Chloroquine

Deferoxamine

Ibuprofen

Iron sorbitol

Nitrofurantoin

Phenazopyridine

Phenolphthalein

Rifampin

Food dyes
Beets (in selected patients)

Blackberries

Food coloring

Metabolities
Bile pigments

Homogentisic acid

Melanin

Methemoglobin

Porphyrin

Tyrosinosis

Urates

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Approach to the patient with red or brown urine

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Algorithm for gross or symptomatic microscopic hematuria in

children

Modified with permission from: Patel, HP, Bissler, JJ. Hematuria in children. Pediatr Clin
North Am 2001; 48:1519. Copyright ©2001 Elsevier.

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Photomicrograph of urine sediment with a red cell cast

Urine sediment showing free red cells and a red cell cast that is
tightly packed with red cells. It is more common for red cell casts
to have fewer red cells trapped within a hyaline or granular cast.
Red cell casts are virtually diagnostic of glomerulonephritis or
vasculitis.
Courtesy of Harvard Medical School.

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Distinguishing extraglomerular from glomerular hematuria

Extraglomerular Glomerular
Color (if macroscopic) Red or pink Red, smoky brown, or "Coca-Cola"

Clots May be present Absent

Proteinuria Usually absent May be present

RBC morphology Normal Dysmorphic

RBC casts Absent May be present

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Phase contrast micrograph showing dysmorphic red cells

in urine sediment

Phase contrast microscopy showing dysmorphic red cells in a

patient with glomerular bleeding. Acanthocytes can be recognized
as ring forms with vesicle-shaped protrusions (arrows).
Courtesy of Hans Köhler, MD.

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Scanning electron micrograph showing dysmorphic red

cells in urine sediment

Scanning microscopy showing dysmorphic red cells in a patient

with glomerular bleeding. Acanthocytes can be recognized as ring
forms with vesicle-shaped protrusions (arrows).
Courtesy of Hans Köhler, MD.

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Phase contrast micrograph showing monomorphic red

cells in urine sediment

Urine sediment viewed by phase contrast microscopy showing

many red cells and an occasional larger white cell with a granular
cytoplasm (arrows). The red cells have a uniform size and shape,
suggesting that they are of nonglomerular origin.
Courtesy of Harvard Medical School.

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