doi:10.1016/j.ucl.2004.04.015

Evaluation of hematuria in children

Kevin E.C. Meyers, MBBCh

Division of Nephrology, Department of Pediatrics, Children’s Hospital of Philadelphia,

University of Pennsylvania School of Medicine, 34th Street and Civic Center Boulevard,

Main Building, 2nd Floor, Philadelphia, PA 19104-4399, USA

The detection of even microscopic amounts of

blood in a child’s urine alarms the patient,

parents, and physician, and often prompts the

performance of many laboratory studies. Hema-

turia is one of the most important signs of renal or

bladder disease, but proteinuria is a more impor-

tant diagnostic and prognostic ﬁnding, except in

the case of calculi or malignancies. Hematuria is

almost never a cause of anemia. The physician

should ensure that serious conditions are not

overlooked, avoid unnecessary and often expen-

sive laboratory studies, reassure the family, and

provide guidelines for additional studies if there is

a change in the child’s course [1]. This article

provides an approach to the evaluation and

management of hematuria in a child [2,3]. Many

tests have been recommended for the child with

hematuria, but no consensus exists on a stepwise

evaluation. Although more research is needed to

resolve certain controversies in management, the

suggested approach aims to detect major or

treatable problems and limit the anxiety, cost,

and energy required by unnecessary testing.

Deﬁnitions

Macroscopic hematuria is visible to the naked

eye, but microscopic hematuria usually is detected

by a dipstick test during a routine examination.

Hematuria is conﬁrmed by microscopic examina-

tion of the spun urine sediment. Microscopic

examination is performed with concentration of

the urinary sediment by centrifugation. Ten milli-

liters of urine is spun at 2000 rpm for 5 minutes.

Nine milliliters is decanted and the sediment

is resuspended and an aliquot examined. The urine

is examined by microscopy by high power ﬁeld

(hpf) that is 400 magniﬁcation. Macroscopic

hematuria often does not require concentration.

Bright-red urine, visible clots, or crystals with

normal-looking red blood cells (RBCs) suggests

bleeding from the urinary tract. Cola-colored

urine, RBC casts, and deformed (dysmorphic)

RBCs suggest glomerular bleeding [4]. An absence

of RBCs in the urine with a positive dipstick re-

action suggests hemoglobinuria or myoglobinuria.

The sensitivity and speciﬁcity of the dipstick

method for detecting blood in the urine vary.

When tested on urine samples in which a prede-

termined amount of blood has been placed, dip-

sticks have a sensitivity of 100 and a speciﬁcity of

99 in detecting one to ﬁve RBCs/hpf [5]. This

corresponds to approximately 5 to 10 intact

RBCs/lL urine [6]. There is no consensus on the

deﬁnition of microscopic hematuria, although

more than 5 to 10 RBCs/hpf is considered

signiﬁcant [7,8]. The author and others recom-

mend that at least two of three urinalyses show

microhematuria over 2 to 3 weeks before further

evaluation is performed [3,9]. The American

Academy of Pediatrics recommends a screening

urinalysis at school entry (4–5 years of age) and

once during adolescence (11–21 years of age) as

a component of well child–care.

Incidence and prevalence

Pediatricians frequently encounter hematuria

in children. Macroscopic hematuria has an esti-

mated incidence of 1.3 per 1000 [2]. Microscopic

hematuria, although more common than gross

E-mail address: [email protected]

doi:10.1016/j.ucl.2004.04.015

Urol Clin N Am 31 (2004) 559–573

hematuria, has a variably reported incidence

depending on the deﬁnition used for making the

diagnosis. The incidence of microscopic hematu-

ria in schoolchildren was estimated at 0.41%

when four urine samples per child were collected

and 0.32% in girls and 0.14% in boys when ﬁve

consecutive urine specimens were analyzed over 5

years [10,11]. Microscopic hematuria in two or

more urine samples is found in 1% to 2% of

children 6 to 15 years of age.

Pathophysiology

Hematuria may originate from the glomeruli,

renal tubules and interstitium, or urinary tract

(including collecting systems, ureters, bladder, and

urethra) (Boxes 1 and 2). In children, the source of

bleeding is more often from glomeruli than from

the urinary tract. RBCs cross the glomerular

endothelial-epithelial barrier and enter the capil-

lary lumen through structural discontinuities in the

capillary wall. These discontinuities seem to be at

the capillary wall–mesangial cell reﬂections [12].In

most cases, proteinuria, RBC casts, and deformed

(dysmorphic) RBCs in the urine accompany he-

maturia caused by any of the glomerulonephriti-

des. The renal papillae are susceptible to necrotic

injury from microthrombi and anoxia in patients

with a hemoglobinopathy or in those exposed to

toxins. Patients with renal parenchymal lesions

may have episodes of transient microscopic or

macroscopic hematuria during systemic infections

or after moderate exercise. This may be the result

of renal hemodynamic responses to exercise or

fever by undetermined mechanisms.

Initial evaluation

Macroscopic hematuria

The evaluation of a child with gross hematuria

diﬀers from that of microscopic hematuria (Fig. 1).

Macroscopic hematuria of glomerular origin usu-

ally is described as brown, tea-colored, or cola-

colored, whereas macroscopic hematuria from the

lower urinary tract (bladder and urethra) is usually

pink or red. Macroscopic hematuria in the absence

of signiﬁcant proteinuria or RBC casts is an

indication for a renal and bladder ultrasound to

exclude malignancy or cystic renal disease. Re-

ferral to a urologist is required when clinical

evaluation and workup indicates that there is

a tumor, a structural urogenital abnormality, or

an obstructing calculus. A urologist also should

evaluate children with recurrent nonglomerular

macroscopic hematuria of undetermined origin

because cystoscopy may be warranted.

Microscopic hematuria

Microscopic hematuria, deﬁned by more than

ﬁve RBCs/hpf, almost always warrants referral to

a nephrologist rather than an urologist. Figs. 2

and 3 give an approach to the evaluation of

asymptomatic and symptomatic microscopic

Box 1. Causes of hematuria in children

Glomerular diseases

Recurrent gross hematuria (IgA

nephropathy, benign familial

hematuria, Alport’s syndrome)

Acute poststreptococcal

glomerulonephritis

Membranoproliferative

glomerulonephritis

Systemic lupus erythematosus

Membranous nephropathy

Rapidly progressive

glomerulonephritis

Henoch-Schonlein purpura

Goodpasture’s disease

Interstitial and tubular

Acute pyelonephritis

Acute interstitial nephritis

Tuberculosis

Hematologic (sickle cell disease,

coagulopathies von Willebrand’s

disease, renal vein thrombosis,

thrombocytopenia)

Urinary tract

Bacterial or viral (adenovirus)

infection–related

Nephrolithiasis and hypercalciuria

Structural anomalies, congenital

anomalies, polycystic kidney

disease

Trauma

Tumors

Exercise

Medications (aminoglycosides,

amitryptiline, anticonvulsants,

aspirin, chlorpromazine, coumadin,

cyclophosphamide, diuretics,

penicillin, thorazine)

560 K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

hematuria. Most children with isolated micro-

scopic hematuria do not have a treatable or serious

cause for hematuria and do not require an

extensive evaluation. The presence of hematuria

must be conﬁrmed by microscopy examination of

spun sediment of urine because other substances

besides blood can produce red or brown urine or

give a false positive dipstick test for blood (Box 3).

Once a positive dipstick result has been con-

ﬁrmed by microscopic examination of spun sedi-

ment of urine, it is advisable to redirect attention

to more speciﬁc aspects of the history and physical

examination (Box 4).

History

A history of dysuria, frequency, urgency, or

ﬂank or abdominal pain suggests a diagnosis of

urinary tract infection or nephrolithiasis. Recent

trauma, strenuous exercise, menstruation, or blad-

der catheterization may account for transient

hematuria. A sore throat or skin infection within

the past 2 to 4 weeks directs the evaluation toward

postinfectious glomerulonephritis. Drugs and

toxins may cause either hematuria or hemoglobin-

uria (Box 5). A careful family history must include

questions about hematuria, hearing loss, hyper-

tension, nephrolithiasis, renal diseases, renal cystic

diseases, hemophilia, sickle cell trait, and dialysis

or transplant.

Physical examination

The presence or absence of hypertension or

proteinuria helps to decide how extensively to

pursue the diagnostic evaluation. If the blood

pressure is normal and the patient is passing

normal amounts of urine, it is unlikely that

microscopic hematuria, whatever its cause, war-

rants immediate treatment. If the blood pressure is

elevated, the hematuria requires a more intensive

diagnostic evaluation. The presence of fever or

costovertebral angle tenderness may indicate a

urinary tract infection. An abdominal mass may

be caused by a tumor, hydronephrosis, multicystic

dysplastic kidney, or polycystic kidney disease.

Macroscopic hematuria with proteinuria suggests

glomerulonephritis. Rashes and arthritis can occur

in Henoch-Schonlein purpura and systemic lupus

erythematosus. Edema is an important feature of

the nephrotic syndrome (Table 1).

Laboratory studies

Only two diagnostic tests are required for

a child with microscopic hematuria: (1) a test for

proteinuria and (2) a microscopic examination of

the urine for RBCs and RBC casts. Children with

macroscopic hematuria require urine culture and

renal imaging by ultrasound. Proteinuria may be

present regardless of the cause of bleeding, but

usually does not exceed 2þ (100 mg/dL) if the only

source of protein is from the blood. This is

especially true if the child has microscope hema-

turia. Patients with 1þ to 2þ proteinuria should be

evaluated for orthostatic (postural) proteinuria. A

patient with more than 2þ proteinuria should be

investigated for glomerulonephritis and nephrotic

syndrome. RBC casts, when present, are a highly

speciﬁc marker for glomerulonephritis, but their

Box 2. Causes of asymptomatic isolated

microscopic hematuria

Common

Undetermined

Benign familial

Idiopathic hypercalciuria

IgA nephropathy

Sickle cell trait or anemia

Transplant

Less common

Alport nephritis

Postinfectious glomerulonephritis

Trauma

Exercise

Nephrolithiasis

Henoch-Schonlein purpura

Uncommon

Drugs and toxins

Coagulopathy

Ureteropelvic junction obstruction

Focal segmental glomerulosclerosis

Membranous glomerulonephritis

Membranoproliferative

glomerulonephritis

Lupus nephritis

Hydronephrosis

Pyelonephritis

Vascular malformation

Tuberculosis

Tumor

(Adapted from Lieu TA, Grasmeder M,

Kaplan BS. An approach to the evaluation

and treatment of microscopic hematuria.

Pediatr Clin North Am 1991;38:579–92.)

561K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

absence does not rule out glomerular disease and

their presence does not prove that glomerular

injury has occurred. RBC casts should be searched

for diligently, however. Distorted, misshapen

erythrocytes (dysmorphic) also suggest a glomeru-

lar origin for bleeding.

Indications for prompt evaluation

The initial evaluation should be directed to-

ward important and potentially life-threatening

causes of hematuria in any child who has any of

the following in addition to hematuria: hyperten-

sion, edema oliguria, signiﬁcant proteinuria (more

than 500 mg per 24 hours), or RBC casts. These

causes include acute postinfectious glomerulone-

phritis (PIGN), Henoch-Schonlien purpura

(HSP), hemolytic-uremic syndrome, membrano-

proliferative glomerulonephritis, IgA nephropa-

thy, and focal segmental glomerulosclerosis.

This initial evaluation should include a com-

plete blood count (hemolytic-uremic syndrome),

throat culture, streptozyme panel and serum C3

concentration (acute poststreptococcal glomeru-

lonephritis), and serum creatinine and potassium

concentrations (if there is renal insuﬃciency). All

children with macroscopic hematuria require re-

nal ultrasound upon presentation. Pending the

results of these tests, the child’s blood pressure

and urine output must be monitored frequently.

If the cause of the hematuria remains unclear

after the results of the above tests have been

obtained, a 24-hour urine collection for protein,

creatinine, and calcium should be obtained. Chil-

dren with microhematuria and protein excretion of

less than 25 mg/dL (6 mg/h/m

) usually do not have

a glomerulopathy and can be considered to have

isolated microscopic hematuria. Some, however,

may have IgA nephropathy, early or mild Alport’s

syndrome, or thin basement membrane disease.

There is no speciﬁc treatment, however, for any of

these conditions. The causes of microscopic hema-

turia with substantial proteinuria include minimal

change nephrotic syndrome, IgA nephropathy,

Alport’s syndrome, membranoproliferative glo-

merulonephritis, membranous nephropathy, and

Macroscopic hematuria

Symptoms and signs of a glomerulonephritis -

edema/hypertension/proteinuria/RBC casts

Yes

Check basic metabolic

panel,complete blood count,

complement C3, albumin,

anti-streptolysin titer, and

streptozyme

Tests consistent with

post infectious

glomerulonephritis

Yes

Supportive

therapy

Refer to a Pediatric

Nephrologist

History of trauma

Yes

CT scan of abdomen/pelvis

Signs/Symptoms of UTI

Urine culture

Renal ultrasound

Yes

Family history of stones

Renal ultrasound

24 hr urine collection

for metabolic stone profile

Renal ultrasound, Urine culture, Test parents for

hematuria, Hemaglobin electophoresis, Urine

calcium/creatine ratio

Yes

Hypertension

Hyperkalemia

Azotemia

Refer to a Urologist

Obstructing stone

Tumor, structural abnormalit

Fig. 1. Evaluation of a child with macroscopic hematuria.

562 K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

focal segmental glomerulosclerosis. Additional in-

vestigations are warranted in this context, some

may require treatment, and referral to a pediatric

nephrologist should be considered.

Diﬀerential diagnosis and management

of macrohematuria

Macroscopic hematuria requires prompt eval-

uation to exclude potentially life-threatening

causes. A urinalysis must be performed to conﬁrm

the presence of RBCs and to look for casts and

crystals. Occasionally, Schistosoma hematobium is

diagnosed by ﬁnding ovae in the urine of an

immigrant child with unexplained macroscopic

hematuria [16]. Painful gross hematuria usually is

caused by infections, calculi, or urologic condi-

tions. Glomerular causes of hematuria are pain-

less. The most common glomerular causes of

gross hematuria in children are poststreptococcal

glomerulonephritis and IgA nephropathy.

A detailed history must be obtained to elicit

the cause of hematuria. An antecedent sore

throat, pyoderma, or impetigo proteinuria, edema,

hypertension, or RBC casts suggests glomer-

ulonephritis. If the antistreptolysin O titer,

streptozyme test, and serum C3 concentration

are informative, the diagnosis is poststreptococcal

glomerulonephritis. If these tests are not informa-

tive, further investigations are warranted to rule

out other causes of glomerulonephritis. IgA ne-

phropathy can cause recurrent macroscopic he-

maturia with ﬂank or abdominal pain and may be

preceded by an upper respiratory tract infection.

Fever, dysuria, and ﬂank pain with or without

voiding symptoms suggests a urinary tract in-

fection, which is the most common cause of gross

hematuria in children presenting to an emergency

room. A CT scan of the abdomen and pelvis must

be obtained promptly with a history of abdominal

trauma and the child must be referred to a urolo-

gist. A family history of renal calculi or severe

renal colic with gross hematuria suggests urinary

calculi. Hypercalciuria can cause recurrent mac-

roscopic or microscopic hematuria in the absence

of calculi on imaging studies. If no obvious cause

is found for macroscopic hematuria by history,

physical, and preliminary studies, the diﬀerential

diagnosis includes hypercalciuria, sickle cell trait,

thin basement membrane disease, calculi, and

vascular or bladder pathology.

Cystoscopic examination in children rarely

reveals a cause for hematuria but should be done

when bladder pathology is a consideration.

Isolated Microscopic Hematuria - Asymptomatic

Repeat urinalysis weekly x

2 (without exercise)

Negative

Follow up urinalysis

with physical exam

Persistent hematuria

Family history of

calculi

Yes

Check urine

calcium/creatinine

ratio

Test parents and

sibs for hematuria

Positive

Benign Familial

Hematuria

If no other concerning

symptoms/signs then follow

with yearly urinalysis

Consider hearing test, renal ultrasound,

and hemaglobin electrophoresis depending

on level of concern

Normal

Fig. 2. Evaluation of a child with asymptomatic microscopic hematuria.

563K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

Cystoscopy to lateralize the source of bleeding is

performed best during active bleeding. In young

girls with recurrent gross hematuria, it is impor-

tant to inquire about a history of child abuse or

insertion of a vaginal foreign body; the genital

area must be examined for signs of injury.

Diﬀerential diagnosis of transient

microhematuria

Blunt abdominal trauma may cause either

microscopic or gross hematuria. Hematuria after

minor blunt abdominal trauma may serve as

a marker for congenital anomalies. In a study of

suspected isolated renal trauma, 11 of 78 children

had congenital anomalies, but only two required

later surgical intervention [17]. A diagnostic study

should be done only if there are at least 50 RBCs/

hpf, however. Although intravenous urography

traditionally has been the study of choice for

suspected, isolated, blunt renal trauma, renal

ultrasonography may be adequate if there are no

other indications for immediate surgical interven-

tion. Children with less than 50 RBCs/hpf are

unlikely to have injuries or congenital anomalies

that require intervention [17,18]. Transient hema-

turia may be associated with strenuous exercise.

The type of activity, as well as activity duration

and intensity, contributes to its development

[19,20]. If the hematuria disappears with rest, no

further investigation is needed.

Diﬀerential diagnosis of persistent

microhematuria

The precise frequencies of occurrence of the

causes of persistent microscopic hematuria have

not been established. Most series have included

patients with macroscopic and microscopic hema-

turia as well as patients with and without pro-

teinuria. In a study of 33 children with persistent

microscopic hematuria, 27 did not have protein-

uria. Two of these had ureteropelvic junction

obstruction, and renal biopsies were done in 21

of the remaining 25 patients, two of which had

IgA nephropathy, one had hereditary nephritis,

eight had normal renal biopsies, and 10 had

nonspeciﬁc abnormalities [21].

The author retrospectively studied 325 children

with isolated persistent microscopic hematuria

Microscopic hematuria (MH) plus

Family history or additional findings

Family history:

Progressive renal disease

and /or

Patient: Presence of casts

or non-postural proteinuria

Hearing test

Serum creatinine, C3, C4

Abnormal results

Refer to Pediatric

Nephrologist/Consider renal

biopsy

Normal

Follow up

urinalysis

Family history: No progressive renal disease

Patient: Isolated microhematuria on urinalysis

Urinary crystals

Family history of stones

Urine calcium/creatinine ratio

Urine calcium/ creatinine ratio

> 0.21 on 2-3 samples

24 hr urine calcium >

4 mg/m

/day

Renal ultrasound

Family history of MH

Normal urine calcium

/creatinine ratio

Observe, repeat

Urinalysis in 6-12

months

No family history of MH,

normal urine calcium/ creatinine

ratio

Observe, repeat urinalysis in 6-

12 months

Negative

Family

member

with MH

Yes

Familial MH

Isolated MH

ercalciuria

Familial MH

Fig. 3. Evaluation of a child with symptomatic microscopic hematuria.

564 K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

referred to the pediatric nephrology outpatient

clinics at the Children’s Hospitals of Buﬀalo and

Philadelphia between 1985 and 1994. Hypercal-

ciuria was present in 11%. Renal ultrasonography

and voiding cystourography (VCUG) was per-

formed in 87% and 24% of children. There were

no clinically signiﬁcant ﬁndings. Primary physi-

cians or urologists ordered 75% of the VCUG

before referral to a nephrologist [22]. In another

study, 2 of 15 patients with persistent microscopic

hematuria progressed to end-stage renal failure

(one with Alport’s syndrome after 14 years and

one with focal segmental glomerulonephritis after

10 years), but it is not clear when in their courses

these patients developed proteinuria. This study

supports the author’s minimalist approach to

children with isolated persistent microscopic he-

maturia (see Fig. 2). Because the most common

diagnoses in children with persistent microscopic

hematuria without proteinuria are benign persis-

tent or benign familial hematuria, idiopathic

hypercalciuria, IgA nephropathy, and Alport’s

syndrome, a more extensive evaluation is indicated

only when proteinuria or other indicators are

present (see Fig. 3).

Management of microhematuria

When there are no indications for immediate

intervention, the parents should be reassured that

there are no life-threatening conditions, that there

is time to plan a stepwise evaluation, and that most

causes of isolated microscopic hematuria in chil-

dren do not warrant treatment. In the author’s

experience, parents have two main concerns when

they learn that their child has microscopic hema-

turia: (1) will chronic kidney damage occur, and

(2) does my child have cancer (or leukemia)?

Addressing these fears allays concerns and expen-

Box 3. Urine color

Dark yellow or orange

Normal concentrated urine

Rifampin pyridium

Dark brown or black

Methemoglobinemia

Bile pigments

Homogentesic acid, thymol, melanin,

tyrosinosis, alkaptonuria

Alanine, cascara, resorcinol

Red or pink urine

RBCs, free hemoglobin, myoglobin,

porphyrins

Benzene, chloroquine,

desferoxamine, phenazopyridine,

phenolphthalein

Beets, blackberries, red dyes in food

Urates

Box 4. Speciﬁc history and physical

examination in a patient with hematuria

History

Trauma (recent bladder catheterization,

blunt abdominal trauma)

Exercise

Menstruation

Recent sore throat, skin infection

Viral illness

Dysuria, frequency, urgency, enuresis

Urine color; stream discolored at

initiation, throughout, or at

termination of micturition

Abdominal pain, costovertebral angle

pain, suprapubic pain

Medications (eg, cyclophosphamide),

environmental toxins, or herbal

compounds

Passage of a calculus

Joint or muscle pain

Family history

Hematuria

Deafness

Hypertension

Coagulopathy

Hemoglobinopathy

Calculi

Renal failure, dialysis, or transplant

Physical examination

Fever, arthritis, rash

Blood pressure

Edema

Nephromegaly

Costovertebral angle tenderness

(Adapted from Lieu TA, Grasmeder M,

Kaplan BS. An approach to the evaluation

and treatment of microscopic hematuria.

Pediatr Clin North Am 1991;38:579–92.)

565K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

sive investigations. The plans for further testing

and follow-up should be stated clearly from the

outset. The dipstick and microscopic urinalysis

should be repeated twice within 2 weeks after the

initial specimen. If the hematuria resolves, no

further tests are needed. If hematuria persists, with

more than ﬁve RBCs/hpf and no evidence of

hypertension, oliguria, or proteinuria on at least

two of three consecutive samples, determination of

the serum creatinine concentration is reasonable.

Renal ultrasonography should be considered as

a screening test because it is noninvasive and

provides tangible information on the presence or

absence of stones, tumors, hydronephrosis, struc-

tural anomalies, renal parenchymal dysplasia,

medical renal disease, inﬂammation of the bladder,

bladder polyps, and posterior urethral valves. The

yield of renal ultrasonography for evaluation of an

asymptomatic child with microscopic hematuria

remains unproven [22]. The value of a normal renal

ultrasonographic examination in terms of reassur-

ance, however, may justify its cost and time.

In the author’s view, intravenous urography is

of little value in the evaluation of persistent

microscopic hematuria because renal ultrasonog-

raphy is as reliable as intravenous urography for

excluding macroscopic lesions. If the serum cre-

atinine concentration and blood pressure are

normal, it is reasonable to defer further inves-

tigations in an asymptomatic child with persistent

microscopic hematuria who does not have hyper-

tension, proteinuria, or RBC casts. The author

suggests a follow-up examination at least every

12 months that includes microscopic urinalysis, a

dipstick test for proteinuria, and blood pressure

measurement.

In a study of 142 children with microscopic

hematuria on two initial urine samples who had two

subsequent urinalyses performed in the subsequent

4 to 6 months, 33 (23%) had persistent hematuria

on both follow-up specimens [21]. The parents’

urine should be tested with dipsticks [23,24] .

Although phase-contrast microscopy and size-par-

ticle discrimination can distinguish glomerular

from nonglomerular sources of hematuria, identi-

ﬁcation of dysmorphic RBC oﬀers little additional

information in the evaluation of microscopic he-

maturia in children. A thoughtful history and

physical examination with microscopic urinalysis

and dipstick for proteinuria provide equal diag-

nostic information. The author cannot recommend

its routine use in the evaluation of microscopic

hematuria in children [25,26].

Many other tests may be considered in the

asymptomatic child with persistent microscopic

hematuria, but the cost and time required for

further testing must be weighed against the poten-

tial beneﬁts, which are subjective and depend on

how much importance the parents and physician

place on establishing a more deﬁnite diagnosis and

prognosis. These considerations apply especially to

the advisability of performing a kidney biopsy on

a patient with isolated microhematuria. Piqueras

and colleagues [27] reviewed the clinical and renal

biopsy ﬁndings in 322 children in whom non-

glomerular causes of hematuria were excluded.

Isolated microscopic hematuria was present in 155

children, 100 of whom had a thin basement

membrane (TBM) or Alport’s syndrome, 12 (7%)

had IgA nephropathy, and 43 (28%) had normal

or clinically insigniﬁcant glomerular ﬁndings. No

child required therapy, but the argument was made

that a precise diagnosis is required for prognosis,

insurance purposes, and genetic counseling. In the

author’s opinion, renal biopsy should be deferred

for this reason unless a speciﬁc indication exists.

Box 5. Drugs and toxins associated with

urine dipsticks positive for blood

Hemoglobinuria

Carbon monoxide

Mushrooms

Naphthalene

Sulfonamides

Tin compounds

Lead

Methicillin

Phenol

Sulfonamides

Turpentine

Ticlodipine [14]

Hematuria

Amitriptylene

Anticoagulants

Aspirin

Chlorpromazine

Cyclophosphamide

Toluene [13]

Ritonavir, indinavir [15]

(Adapted from Lieu TA, Grasmeder M,

Kaplan BS. An approach to the evaluation

and treatment of microscopic hematuria.

Pediatr Clin North Am 1991;38:579–92.)

566 K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

Isolated microscopic hematuria in the absence of

a family history of hematuria in a close relative and

episodes of macroscopic hematuria is unlikely to

be associated with abnormal renal biopsy ﬁndings.

The main exceptions are IgA nephropathy and

TBM nephropathy, but there are no speciﬁc treat-

ments for these conditions.

Speciﬁc conditions

This section focuses on the more common

causes of hematuria in children and is organized

according to the anatomic location for the bleed-

ing. Box 6 outlines a suggested approach for

referral of a child with hematuria.

Glomerular causes of hematuria

Postinfectious glomerulonephritis

Patients with acute PIGN often present with

acute onset of tea-colored urine (macroscopic

hematuria) consistent with glomerular bleeding,

but the hematuria occasionally may be only

microscopic [28]. Patients with PIGN may be

asymptomatic or they may complain of malaise,

headache, nausea, vomiting, abdominal pain, and

oliguria. The physical examination may reveal

edema and an elevated blood pressure that can be

severe enough to cause encephalopathy. PIGN is

accredited most commonly to pharyngitis or skin

infection with Group A beta-hemolytic strepto-

cocci.

Clinical features of the nephritis manifest 7 to 21

days after the preceding infection. Antistreptolysin

O titers may be negative early in the course, but the

Table 1

Distinguishing features of glomerular and nonglomerular hematuria

Feature Glomerular hematuria Nonglomerular hematuria

History

Burning on micturition No Urethritis, cystitis

Systemic complaints Edema, fever, pharyngitis,

rash, arthralgias

Fever with urinary tract infections

severe pain with calculi

Family history Deafness in Alport’s

syndrome, renal failure

Usually negative; may be positive with calculi

Physical examination

Hypertension Often present Unlikely

Edema May be present No

Abdominal mass No Important with Wilms’ tumor,

polycystic kidneys

Rash, arthritis Lupus erythematosus,

Henoch-Schonlein

Urine analysis

Color Brown, tea, cola Bright red

Proteinuria Often present No

Dysmorphic red blood cells Yes No

Red blood cell casts Yes No

Crystals No May be informative

Box 6. A suggested approach for referral

of a child with hematuria

Nephrologist

Acute poststreptococcal

glomerulonephritis if the patient

has hypertension, azotemia, or

hyperkalemia

Other forms of glomerulonephritis

(particularly if the patient has

proteinuria, hypertension, or

persistent hypocomplementemia)

Family history of renal failure

Systemic disease

Urologist

Reassurance

Abnormal genitourinary anatomy

Trauma

Stones (nephrologist for metabolic

work-up)

Tumor

Nonglomerular gross hematuria

567K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

streptozyme test is often positive within 10 days of

the onset of symptoms [29]. Almost all patients have

decreased levels of C3 early in the clinical course that

normalize 6 to 8 weeks later. The C4 concentration is

usually normal or only slightly decreased. If the C3

is persistently low, the patient should be furth er

investigated for other causes of a persistent hypocom-

plementemic glomerulonephritis, including membra-

noproliferative glomerulonephritis, systemic lupus

erythematosus, and chronic bacteremia. Urinalysis

typically reveals RBC casts and proteinuria. Blood

urea nitrogen and creatinine can be normal or

elevated. In most patients hematuria and proteinuria

resolves within a few weeks. Microscopic hematuria

maypersistforaslongas2years.Theprognosisis

excellent. There are no data that indicate an untoward

outcome of PIGN in a patient whose only

manifestation was microscopic hematuria.

Henoch-Schonlein purpura

Approximately half of children with a clinical

diagnosis of HSP manifest renal involvement [30].

Renal manifestations include hematuria, protein-

uria, nephrotic syndrome, glomerulonephritis, and

acute renal failure. Hematuria and proteinuria are

usually transient but may persist for several

months. Relapses and remissions are seen during

the course of the disease and may manifest with

episodes of gross hematuria. The long-term prog-

nosis of HSP directly depends on the severity of

renal involvement. In an unselected population of

children with HSP, an estimated 2% develop long-

term renal impairment [31]. This ﬁgure is consider-

ably higher in specialized pediatric centers [32]. All

patients with HSP who have renal involvement

should be referred to a pediatric nephrologist.

IgA nephropathy

IgA nephropathy is probably the most common

cause of hematuria in children [33]. The condition

is diagnosed by histopathologic demonstration of

mesangial deposition of IgA. IgA nephropathy

usually is detected after periods of gross hematuria

that follow minor infections [34]. Microscopic

hematuria may be present between episodes of

gross hematuria. In a school-screening program in

Japan, dipstick urinalysis detects most children

with microscopic hematuria who have IgA ne-

phropathy on renal biopsy [35]. Predictors of

a poorer outcome include crescentic glomerulone-

phritis and an older age of onset, hypertension,

and nephrotic range proteinuria. There is also

evidence suggesting that recurrent bouts of mac-

roscopic hematuria predict a more guarded out-

come in IgA nephropathy [36]. The prognosis of

IgA nephropathy varies, and up to one third of

children have a guarded long-term renal prognosis

[37]. There is no speciﬁc treatment for IgA

nephropathy and no evidence supports the need

to make a deﬁnitive diagnosis in a child whose

only manifestation is microscopic hematuria. The

author disagrees with Schena’s [38] and Piqueras’s

[39] recommendation that a renal biopsy should

be done in patients with microscopic hematuria

and suspected IgA nephropathy to conﬁrm the

diagnosis and to increase awareness of the prog-

nosis of patients with IgA nephropathy in the

Western world. In a few patients, IgA nephropa-

thy may be inherited, and has been localized to

6q22-23 [40,41].

Rapidly progressive glomerulonephritis

Rapidly progressive glomerulonephritis presents

with symptoms and signs similar to PIGN, and

although uncommon, requires the urgent atten-

tion of a pediatric nephrologist. Laboratory

studies show acute renal failure, and renal biopsy

demonstrates glomerular crescents. Untreated

RPGN can result in end-stage renal disease

(ESRD) in a few weeks. Many of the causes of

glomerulonephritis listed in Fig. 1 can present

with rapid progression, or RPGN can be idio-

pathic [42]. Prompt diagnosis and pulsed methyl-

prednisolone therapy may prevent progression to

ESRD [43].

Alport hereditary nephritis

Alport’s syndrome is a progressive, inherited

glomerulonephritis accounting for 1% to 2% of

patients who develop ESRD, with an estimated

gene frequency of approximately 1 in 5000 [44].

Alport’s syndrome is characterized by episodes of

recurrent or persistent microscopic hematuria,

occasionally gross hematuria, proteinuria, pro-

gressive renal insuﬃciency, and progressive,

high-frequency, sensorineural hearing loss. The

phenotype and the course vary widely. Ocular

defects include anterior lenticonus and yellow-

white to silver ﬂecks within the macular and

midperipheral regions of the retina [45]. Hematu-

ria that is usually microscopic is the usual initial

ﬁnding in children. In the absence of RBC casts or

proteinuria, the diagnosis may be delayed or

unsuspected, but this does not have serious

consequences for the child unless there are hearing

problems.

A careful family history and urine examina-

tions must be obtained in every patient who

568 K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

presents with microscopic hematuria. If there is

any reason to suspect familial renal disease,

a hearing test should be done to prevent speech

or educational handicap. Men manifest signs and

symptoms earlier than women, and approximately

30% can progress to ESRD. Patients who receive

a renal allograft have a small risk for developing

Goodpasture disease posttransplant [46]. Some

women may have a hearing deﬁcit without any

urinary abnormalities. Alport’s syndrome is a

genetically heterogeneous disease, usually is in-

herited as an X-linked semidominant trait, caused

by mutations in COL4A5 gene on the X-chromo-

some, and in less than 10% of cases is caused by

mutations of the COL4A3 or the COL4A4 gene

on chromosome 2q.

Thin glomerular basement membrane nephropathy

Thin basement membrane nephropathy

(TBMN) or benign familial hematuria is the most

common cause of persistent glomerular bleeding in

children and occurs in at least 1% of the popula-

tion [47]. Benign familial hematuria may be

inherited in an autosomal dominant or autosomal

recessive manner, and may be associated with

mutations in type IV collagen [48,49]. Proteinuria,

progressive renal insuﬃciency, hearing deﬁcits, or

ophthalmologic abnormalities almost never occur

in patients with TBMN or their family members

[50]. The hematuria is usually microscopic, the

RBCs may be dysmorphic, and there may be RBC

casts. Occasionally, frank hematuria may occur

with an upper respiratory tract infection. The

histopathologic changes are thinning of glomeru-

lar basement membranes. A renal biopsy is war-

ranted in TBMN only if there are atypical features,

or if IgA disease or X-linked Alport’s syndrome

cannot be excluded clinically [47].

Renal parenchymal cauises of hematuria

Tumors

Children with Wilms’ tumor most commonly

present with ﬂank mass or macroscopic hematu-

ria. Although a tumor is listed frequently in the

diﬀerential diagnosis of hematuria, neither the

author’s search of the literature nor the author’s

experience has produced documented cases of

tumors presenting with isolated microscopic he-

maturia. Bladder tumors usually manifest with

voiding diﬃculties or occasionally with macro-

scopic hematuria [51].

Nephrocalcinosis

Nephrocalcinosis implies an increase in calcium

content in the kidney and is distinct from urolith-

iasis, although the two conditions often coexist.

Nephrocalcinosis may be focal, occurring in an

area of previously damaged parenchyma, or

generalized. It is often associated with hyper-

calciuria. The most frequent cause of nephrocalci-

nosis is prematurity with and without furosemide

treatment [52]. Nephrocalcinosis associated with

hyperoxaluria involves the cortex and medulla,

whereas the corticomedullary junction is involved

most often with metabolic disease. The clinical

manifestations of nephrocalcinosis include ab-

dominal pain, dysuria, incontinence, and urinary

tract infection in more than one third of patients.

Microscopic hematuria usually occurs in the

context of hypercalciuria or coexistant renal stone

disease [53]. The diagnosis of nephrocalcinosis

usually is made by renal ultrasonography [54].

The oﬀending agent (loop diuretic, excess vitamin

D) must be withdrawn if possible, and any

underlying disorder (distal renal tubular acidosis)

must be treated. Nephrocalcinosis rarely pro-

gresses to end stage renal failure.

Interstitial nephritis

Interstitial nephritis in children with associated

microscopic or macroscopic hematuria is uncom-

mon. Analgesics and antibiotics are implicated

most frequently with resolution occurring after

discontinuation of the oﬀending medication

[55,56].

Cystic renal disease

Cysts often are discovered incidentally after

mild trauma or when abdominal ultrasound is

performed for other indications [57]. Cysts may be

solitary, associated with dysplasia, or associated

with polycystic renal disease. Patients with cystic

renal disease or with a family history of cystic

disease should be referred to a pediatric nephrol-

ogist. Bleeding associated with cystic disease may

be considerable and may require immediate neph-

rologic or urologic evaluation.

Hypercalciuria

An association between hematuria and hyper-

calciuria was ﬁrst noted in 1981 in children with

asymptomatic macroscopic or microscopic hema-

turia without signs of renal stones [58,59]. These

children had increased urinary excretion calcium

despite normal serum calcium levels. Some were

otherwise asymptomatic, but others eventually

developed urolithiasis. Because of this, the

569K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

measurement of urinary calcium excretion has

become a standard part of the evaluation of

hematuria in children.

Many conditions can result in hypercalciuria,

including hyperparathyroidism, immobilization,

vitamin D intoxication, and idiopathic hyper-

calciuria. (See later discussion and recent reviews

of idiopathic hypercalciuria [60,61].)

Idiopathic hypercalciuria may result from

a tubular leak of calcium (renal hypercalciuria)

or from increased gastrointestinal absorption of

calcium (absorptive hypercalciuria). The mecha-

nism whereby hypercalciuria causes hematuria is

unclear. It has been assumed either that hematuria

is the result of irritation of the uroepithelium by

microcalculi or that microscopic areas of neph-

rocalcinosis cause bleeding. Urine erythrocytes

are shaped normally and RBC cast are absent.

There is often a family history of renal stones, and

some authors recommend evaluation of parents

and siblings for hypercalciuria. In contrast to

benign, idiopathic hematuria, macroscopic bleed-

ing and occasional blood clots may be seen in

patients with hypercalciuria. Symptoms may in-

clude dysuria, suprapubic pain, or renal colic. The

author does not restrict calcium in children

because osteopenia may result, and reserves ther-

apy with thiazide diuretics (to enhance calcium

reclamation from the glomerular ﬁltrate) for

patients with recurrent episodes of macroscopic

hematuria or a family history of urolithiasis, or

those who develop a stone [62].

Renal transplant

Children with renal transplants are at risk for

developing urolithiasis, the only manifestation of

which may be hematuria [63]. Review of 21 patients

showed that one third had persistent microscopic

hematuria. Patients with and without hematuria

had similar baseline characteristics. The etiology

of hematuria was pre-existing (one patient), re-

current IgA nephropathy (one patient), cytomeg-

alovirus nephritis (one patient), and unexplained

(four patients). None had renal calculi or hyper-

calciuria. Three of the four patients with un-

explained hematuria have chronic allograft

nephropathy, and the fourth (original disease

dysplasia) had hypocomplementemia. Five years

after onset of hematuria, all patients are alive with

stable allograft function. Causes of posttransplant

hematuria, although diverse, are stone disease in

less than 2% of patients. Whether chronic allo-

graft nephropathy causes hematuria remains to be

determined. Renal biopsies should performed to

look for recurrent or de novo glomerulonephritis

with onset of hematuria if proteinuria or de-

terioration of renal function is seen.

Urinary tract and vascular infection

In children the most common cause of hema-

turia is urinary tract infection. (Please see the

article by Shortliﬀe elsewhere in this issue for

further exploration of urinary infection.)

Trauma

Pelvic fractures and abdominal/chest injuries

help identify patients who require evaluation of

the genitourinary tract. The need for genitouri-

nary tract evaluation in pediatric trauma patients

is based as much on clinical judgment as on the

presence of hematuria [64]. Children with micro-

scopic hematuria of greater than 50 RBC/hpf or

macroscopic hematuria, even in the presence of

a benign abdominal examination, should undergo

imaging with an abdominal CT scan [18]. Signif-

icant renal injuries are unlikely in pediatric

patients with blunt renal trauma but no gross or

less than 50 RBC/hpf microscopic hematuria [18].

Most children with renal injury are managed

conservatively [65]. When blood is present at the

urethral meatus, cystourethrography is required

to look for urethral or bladder injury [66].

Hemangiomas and polyps

Hemangiomas in the urinary tract may cause

hematuria, but these are often impossible to locate

and are only clinically signiﬁcant if there is gross

bleeding; therefore, hemangiomas require diag-

nostic testing and treatment only if they manifest

with macroscopic hematuria [67]. The most com-

mon presenting symptoms of urinary tract polyps

are hematuria and urinary tract obstruction.

Transurethral resection is curative [68].

Loin pain hematuria syndrome

Loin pain hematuria syndrome (LPHS) was

ﬁrst reported in 1967 by Little and colleagues [69]

and refers to episodes of unilateral or bilateral

lumbar pain accompanied by macroscopic or

microscopic hematuria. The diagnosis is made by

exclusion after patients are shown to have normal

renal function, normal genitourinary system, no

infection, no malignancy, no hypercalciuria or

nephrolithiasis, and no previous trauma. Most

patients are women between 20 and 40 years of

age, but there are reports of LPHS in children

[70,71]. The pathogenesis of LPHS is unresolved;

although a vascular cause seems most likely, renal

570 K.E.C. Meyers / Urol Clin N Am 31 (2004) 559–573

biopsy is not helpful [72]. The symptoms of LPHS

are similar to those found in parents of children

with Munchhausen syndrome by proxy (MSBP).

MSBP must be excluded in all children where

LPHS is considered. Almost 50% of patients with

LPHS have psychopathologic disturbances

[73,74]. The author agrees with Gusmano [75] in

questioning the existence of LPHS, particularly in

children.

Idiopathic urethrorrhagia

Urethrorrhagia usually presents in prepubertal

boys. Symptoms included urethrorrhagia (termi-

nal uretheral hematuria) and dysuria (33%).

Cystourethroscopy reveals bulbar urethral inﬂam-

mation. Routine radiographic, laboratory, and

endoscopic evaluation is unnecessary for evaluat-

ing urethrorrhagia. Spontaneous resolution oc-

curs in over 90% of children. Watchful waiting is

indicated. In children with prolonged urethror-

rhagia, evaluation should be considered because

urethral stricture may be identiﬁed [76].

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