Hematuria

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Hematuria

Author: Deogracias Pena, MD, Medical Director of Dialysis, Cook Children's

Medical Center; Clinical Associate Professor, Department of Pediatrics,

Texas Tech University School of Medicine

Deogracias Pena, MD, is a member of the following medical societies:

American Academy of Pediatrics, American Medical Association, and American

Society of Pediatric Nephrology

Editor(s): Neiberger, MD, PhD, Director of Pediatric Renal Stone

Disease Clinic, Associate Professor, Department of Pediatrics, University of

Florida and Shands Hospital; Konop, PharmD, Clinical Assistant

Professor, Department of Pharmacy, Section of Clinical Pharmacology,

University of Minnesota; Spitzer, MD, Professor, Department of

Pediatrics, Albert Einstein College of Medicine; Director of NIH Training

Program, Children's Hospital at Montefiore Medical Center; Trachtman,

MD, Program Director, Pediatrics Research, Schneider Children's Hospital,

Professor, Department of Pediatrics, Division of Nephrology, Albert Einstein

College of Medicine; and Craig B Langman, MD, Head, Division of Pediatric

Nephrology, Children's Memorial Hospital of Chicago; Professor, Department

of Pediatrics, Northwestern University School of Medicine

Background:

Hematuria is one of the most common urinary findings that bring children to

the attention of the pediatric nephrologist. Generally, hematuria is defined

as the presence of 5 or more red blood cells (RBCs) per high-power field in

3 of 3 consecutive centrifuged specimens obtained at least 1 week apart. In

the office setting, a positive reaction on the urine dipstick test is

usually the first indication of the presence of hematuria. Hematuria can be

gross (ie, the urine is overtly bloody, smoky, or tea colored) or

microscopic. It may be symptomatic or asymptomatic, transient or persistent,

and either isolated or associated with proteinuria and other urinary

abnormalities.

Pathophysiology:

The etiology and pathophysiology of hematuria are varied. For instance,

hematuria of glomerular origin may be the result of a structural disruption

in the integrity of glomerular basement membrane caused by inflammatory or

immunologic processes. Chemicals may cause toxic disruptions of the renal

tubules, while calculi may cause mechanical erosion of mucosal surfaces in

the genitourinary tract, resulting in hematuria.

History:

The first step in the evaluation of hematuria is a detailed review of the

history and a thorough physical examination. A history of fever, abdominal

pain, dysuria, frequency, and recent enuresis in older children may point to

a urinary tract infection as the cause of hematuria. A history of recent

trauma to the abdomen may be indicative of hydronephrosis. A history of a

recent throat or skin infection may suggest the diagnosis of postinfectious

glomerulonephritis. Information regarding exercise, menstruation, recent

bladder catheterization, intake of certain drugs or toxic substances, or

passage of a calculus also may assist in the differential diagnosis. Because

certain diseases presenting with hematuria are inherited or familial, it is

important to ask for a family history suggestive of Alport syndrome,

collagen vascular diseases, urolithiasis, or polycystic kidney disease.

Causes:

Hematuria can be of glomerular or nonglomerular origin. Brown-colored urine,

RBC casts, and dysmorphic (small deformed, misshapen, sometimes fragmented)

RBCs and proteinuria are suggestive of glomerular hematuria. Reddish or pink

urine, passage of blood clots, and eumorphic (normal sized, biconcavely

shaped) erythrocytes are suggestive of a nonglomerular bleeding site.

Potential causes of hematuria in children include the following:

Glomerular hematuria

Thin basement membrane disease (benign familial hematuria)

Alport syndrome

IgA nephropathy

Hemolytic uremic syndrome

Postinfectious glomerulonephritis

Membranoproliferative glomerulonephritis

Lupus nephritis

Anaphylactoid purpura (Henoch-Schönlein purpura)

Nonglomerular hematuria

Fever

Strenuous exercise

Mechanical trauma (masturbation)

Menstruation

Foreign bodies

Urinary tract infection

Hypercalciuria/urolithiasis

Sickle cell disease/trait

Coagulopathy

Tumors

Drugs/toxins

Anatomic abnormalities (hydronephrosis, polycystic kidney disease, vascular

malformations)

Acute Poststreptococcal Glomerulonephritis

Alport Syndrome

Appendicitis

Bladder Anomalies

Escherichia Coli Infections

Hemolytic-Uremic Syndrome

IgA Nephropathy

Pyelonephritis

Renal Cortical Necrosis

Sickle Cell Anemia

Tuberculosis

Ureteropelvic Junction Obstruction

Urinary Tract Infection

Urolithiasis

Wilms Tumor

The following are short descriptions of the more common conditions

associated with hematuria in children:

Hypercalciuria

Approximately 30% of children with isolated hematuria may have elevated

urinary calcium levels. Hematuria can be either gross or microscopic, and

may or may not be associated with dysuria. A history of " sandy urine " or

actual passage of calculi is sometimes elicited.

A spot urine calcium-to-creatinine ratio of more than 0.2 is considered

abnormal. It should be remembered that the ratio varies with age, being on

average 0.86 in infants younger than 7 months, 0.6 in children aged 7-18

months, and 0.42 in children aged 19 months to 6 years. A 24-hour urine

collection is recommended if the ratio is high.

An excretion rate of more than 4 mg/kg/d is considered abnormal. Therapy

consists of reduction in calcium intake (when excessive) to amounts

consistent with the recommended daily allowance (RDA) for age and/or

prescription of thiazide diuretics.

IgA nephropathy

IgA nephropathy (ie, Berger nephropathy) is currently the most common cause

of chronic glomerulonephritis in the world. It usually presents with

painless intermittent gross hematuria, followed by persistent microscopic

hematuria. Colicky abdominal or loin pain may occur in some patients who

develop clots in the genitourinary tract. The episode of gross hematuria

often is preceded by an upper respiratory infection. Depending on the

severity of the disease, hypertension, proteinuria, and elevation of serum

creatinine may ensue. In some cases IgA nephropathy may present with only

microscopic hematuria, asymptomatic microscopic hematuria and proteinuria,

acute nephritic syndrome, nephrotic syndrome, or a mixed nephritis-nephrotic

syndrome.

The disease appears to be less common in black individuals. A slight male

preponderance exists. Progression to chronic renal failure and end-stage

renal disease has been reported to occur in 20-50% of patients, usually 10

or more years from diagnosis. The serum IgA level is elevated in 30-40% of

patients, but it is not sufficient to establish the diagnosis. A kidney

biopsy with the characteristic deposition of IgA in the glomerular mesangium

is diagnostic. No effective treatment strategy exists, although prednisone,

fish oils, azathioprine, danazol, dipyridamole, and antioxidants (eg,

vitamin E) have been used with inconclusive results.

Henoch-Schönlein purpura

Some authors believe that Henoch-Schönlein purpura (HSP, anaphylactoid

purpura) shares a similar pathophysiology with IgA nephropathy. However,

prominent vasculitis and purpura are present only in HSP.

The peak incidence is approximately age 4-5 years. A slight male

preponderance is observed. Its onset is preceded by an upper respiratory

infection in at least 30% of patients. Purpuric palpable rash is seen

predominantly on the posterior aspects of the body and lower extremities.

Abdominal pain, joint pain, and swelling are often present. Urinalysis

usually reveals microscopic hematuria and sometimes proteinuria. Hematuria

is likely related to deposition of IgA immune complexes and associated

inflammatory processes in the glomerular mesangium. Measurements of

complement 3 (C3) and antinuclear antibodies (ANA) levels may be needed to

rule out systemic lupus erythematosus.

The disease is usually self-limited and requires no treatment. In children

with nephritic and/or nephrotic syndrome, it may be necessary to give

antihypertensives to control hypertension, diuretics to relieve excessive

fluid retention, and corticosteroids to relieve the inflammation of the

joints and the intensity of the purpuric rash. Some cases of HSP,

particularly those that present with nephritis and/or nephrotic syndrome,

may progress to chronic renal failure.

Hemolytic uremic syndrome

The hemolytic uremic syndrome (HUS) is a common cause of acute renal failure

in children. The classic description is of a child that develops a

thrombocytopenic microangiopathic hemolytic anemia and renal failure after a

preceding bout (1-15 d) of often bloody gastroenteritis. Gross hematuria may

be observed in some cases, but the more usual finding is microscopic

hematuria.

HUS generally is classified into the more common diarrhea-associated HUS (D+

HUS) and the atypical (D- HUS). D+ HUS is caused by shiga toxin produced by

Escherichia coli O157:H7. It is rare in blacks and has a female

preponderance. The disease occurs mostly during the summer and the autumn

seasons. Although ingestion of undercooked contaminated ground beef products

is the most common source of infection, cases have been reported after the

ingestion of raw milk, fruits, and vegetables in contact with manure.

Infection has also been reported after swimming in pools or lakes and after

exposure to the pathogen in nursing homes and day care centers.

The disease process begins when Shiga toxin is absorbed through damaged

colonic mucosa and binds to glycophospholipid globotriaosyl ceramide (Gb3)

receptors in vascular endothelial cells. These are internalized by

endocytosis, and inactivation of 28S ribosomal subunits, inhibition of

protein synthesis, and cell death results. In addition, lipopolysaccharides

(released by verotoxin-producing E coli) also are absorbed, resulting in the

release of inflammatory mediators. The end result is cell death, increased

procoagulant activity, thrombocytopenia, renal vascular microthrombi

formation, and the characteristic picture of HUS. Although involvement of

the gastrointestinal tract, kidney, and the hematologic system are commonly

observed, involvement of other organs such as the liver, pancreas, gall

bladder, lungs, and the central nervous system have frequently been

reported.

Treatment is mainly supportive. Meticulous care of electrolyte

abnormalities, hypertension, and, if necessary, dialysis has resulted in a

dramatic decrease in mortality rates-from 40% in the decades when it was

first described to the 5-10% seen today.

Postinfectious glomerulonephritis

This is probably the most common cause of gross hematuria in children.

Although the disease often is precipitated by various pathogens (viral or

bacterial), an antecedent infection (1-4 wk) with a nephritogenic strain of

group A beta-hemolytic streptococci is often the culprit.

The child frequently has a history of a recent pharyngitis or skin infection

1- 2 weeks before the onset of symptoms. Streptococcal pharyngitis is more

common in the winter and early spring and seen mostly in children aged 5-15

years. On the other hand, skin infections (pyoderma) frequently occur in

younger children in the summer and fall.

Gross hematuria is seen in 25-33% of cases and may range from light pink to

a dark " tea " color. Eighty-five percent of patients may develop edema.

Hypertension and oliguria are common. RBCs (most are small and dysmorphic)

and RBC casts are common in the urine. A fresh urine sample should be used

for this purpose. Proteinuria also may be noted but is usually not in the

nephrotic range. Elevation of antistreptolysin (ASO) serum levels (80% of

untreated patients) and depressed C3 levels are helpful in providing

evidence of an antecedent streptococcal infection. Since ASO may not be

detected in pyoderma because the antibody can be bound to lipids in the

skin, anti-DNAse B may be more helpful in establishing a diagnosis in these

cases. Serial measurements (at least 1 wk apart) of these serologic markers

may lend support to the assumption that a prior streptococcal infection is t

emporally related to the nephritis.

Treatment is mainly supportive. Strict fluid and salt restriction should be

observed because the main problems encountered are often caused by fluid

retention. Diuresis with loop diuretics is indicated to alleviate volume

expansion. Vasodilators, calcium channel blockers, beta-blockers, or

angiotensin-converting enzyme inhibitors may be indicated in the management

of hypertension.

The C3 levels typically normalize in 68 weeks. Gross hematuria quickly

disappears, but microscopic hematuria may persist for years. Most

investigators agree that the great majority of children with PSGN heal

without any residual damage. A kidney biopsy is not needed unless a disease

other than PSGN is suspected, the child presents with nephrotic syndrome and

nephritis, or the child does not recover promptly.

Systemic lupus erythematosus

Approximately two thirds of children with systemic lupus erythematosus (SLE)

have renal involvement. Various combinations of gross hematuria and

proteinuria (sometimes in the nephrotic range) and hypertension are found.

However, the degree of hematuria does not necessarily directly correlate

with the severity of the renal lesions.

The incidence of SLE is 0.6 per 100,000 children and adolescents, with a

higher frequency among persons of African, Hispanic, or Asian descent. While

more common in girls, the female predominance is not as pronounced in

children as in adults. No exact pathogenic mechanism explains the

manifestations of SLE. However, it is generally accepted that environmental

stimuli interacting with certain genetic determinants or acquired immune

defects result in a polyclonal B cell immune response, with a variety of

antibodies being deposited in target tissues, such as the kidney and other

organs. Various serologic and hematologic abnormalities are noted and may

include anemia, thrombocytopenia, decreased serum complement levels,

elevated ANA levels and anti-double stranded DNA levels.

The degree of renal involvement should be determined histologically. The

currently accepted classification is based on the World Health Organization

(WHO) system and some modification using the International Study of Kidney

Disease in Children (ISKDC) subclassification. Findings may range from mild

glomerulitis to diffuse proliferative glomerulonephritis. Treatment and

prognosis of the renal disease depends on the histologic classification. The

drug therapy chosen depends on the severity of the disease and my include

steroids, alkylating agents (cyclophosphamide), antimalarials, calcineurin

inhibitors, and, recently, mycophenolate mofetil.

Lab Studies:

Urinalysis/urine culture

The urine dipstick test is currently one of the most useful and sensitive

tools in detecting hematuria. This test is based on the peroxidase activity

of hemoglobin. It can detect trace amounts of hemoglobin (rather than the

presence of RBCs) and myoglobin. False-positive results can occur (certain

dyes or drugs, beets, oxalates).

A microscopic analysis of the urine should follow a positive dipstick test.

A freshly voided urine specimen should be used for this purpose. A 10- to

15-mL aliquot of the urine is spun in a centrifuge at 1500 rpm for about 5

minutes. The supernatant is decanted and the sediment is resuspended in the

remaining liquid. Careful examination of the urine sample then is conducted

under high-power magnification. All noncellular and cellular elements seen

should be noted and recorded. The presence of more than 5 RBCs per

high-powered field generally is considered abnormal. The detection of RBC

casts is indicative of a glomerulotubular source of hematuria. The absence

of RBCs and RBC casts despite a positive dipstick test is suggestive of

hemoglobinuria or myoglobinuria.

Other cellular elements in the urinary sediment (eg, WBCs, WBC casts)

suggest a diagnosis of urinary tract infection. In this latter instance, a

urine culture must be performed to determine the causative organism.

Crystals, bacteria, protozoa, and other elements also may be seen.

Phase contrast microscopy: A careful examination of the urine for the

presence of a significant number of dysmorphic RBCs suggests a renal

(glomerular) source of the hematuria. A urine sample that predominantly

contains eumorphic RBCs suggests an extrarenal (nonglomerular) source. This

test has been reported to have a sensitivity of 83-95% and a specificity of

81-95%. The sensitivity and specificity may vary from one examiner to

another.

Blood urea nitrogen/serum creatinine: Elevated levels of BUN and creatinine

suggest significant renal disease as the cause of hematuria.

Hematologic and coagulation studies: Complete blood counts (CBC) and

sometimes platelet counts may be performed in selected patients with a clear

history of a bleeding disorder. In general, coagulation studies and CBCs

often do not add additional information in the evaluation of hematuria. In

certain populations, a sickle cell preparation or a hemoglobin

electrophoresis may be useful in establishing the diagnosis of sickle cell

disease or trait.

Urine calcium: Hypercalciuria is a relatively common finding in children.

Measurement of the urine calcium excretion using either a timed 24-hour

urine collection for calcium or a spot urine calcium-creatinine ratio can be

helpful in establishing hypercalciuria as a cause of hematuria. A calcium

excretion of more than 4 mg/kg/d or a urine calcium-creatinine ratio of more

than 0.21 are considered abnormal.

Serologic testing: A high ASO titer suggests a recent streptococcal

infection. Anti-DNase B levels also are indicative of a recent group B

streptococcal infection and may be positive even when the ASO level is

normal. This latter statement is relevant in poststreptococcal

glomerulonephritis secondary to a skin infection. ANA titers, complement

levels, and double-stranded DNA (dsDNA) are most helpful in children with

suspected systemic lupus erythematosus nephritis or membranoproliferative

glomerulonephritis.

The laboratory tests ordered for the evaluation of hematuria must be based

on the clinical history and the physical examination. The physician should

avoid automatically requesting tests that may be unnecessary.

Imaging Studies:

Renal and bladder sonography: Urinary tract anomalies, such as

hydronephrosis, hydroureter, nephrocalcinosis, and urolithiasis are detected

readily by sonography. Compared to other imaging studies, sonography is

rapid, noninvasive, readily available, and devoid of exposure to radiation.

In individuals with severe obesity, a more accurate definition of renal

structures and surrounding organs can only be achieved with computerized

tomography (CT).

Other imaging studies: A spiral CT scan is particularly useful in the

detection of urolithiasis. Voiding cystourethrograms are valuable in

detecting urethral and bladder abnormalities that may result in hematuria

(eg, cystitis). Radionuclide studies can be helpful in the evaluation of

obstructing calculi. Intravenous urography rarely contributes additional

information in the evaluation of hematuria and may unnecessarily expose the

child to ionizing radiation.

Procedures:

Kidney biopsy

A kidney biopsy rarely is indicated in the evaluation of isolated

asymptomatic hematuria. Most studies reveal minimal histopathological

abnormalities in such children. In a survey of pediatric nephrologists in

North America, only 5% of responders indicated that they would perform a

kidney biopsy on a child with asymptomatic hematuria. The main reasons for

performing a biopsy in that survey were academic interest, parental pressure

for a diagnosis, and concern for future economic impact on the child. On the

other hand, the simultaneous presence of proteinuria, elevated serum

creatinine, hypertension, a suspicious clinical history, or other

imaging/laboratory abnormalities may justify a kidney biopsy.

Thus, relative indications for performing a kidney biopsy in patients with

hematuria are as follows:

Significant proteinuria

Abnormal renal function

Recurrent persistent hematuria.

Serologic abnormalities (abnormal complement, ANA, or dsDNA levels).

Recurrent gross hematuria.

A family history of end stage renal disease

Histologic Findings:

In most patients, a renal biopsy is either normal or reveals minor changes,

such as thin glomerular basement membranes, focal glomerulonephritis, or

mild mesangial hypercellularity. In a minority of patients, histologic

findings, together with historical or serologic data, may point to specific

conditions

SLE:

Mild glomerulitis, proliferative changes, immune complex deposition,

crescents, immunoglobulin deposition

Hematuria, proteinuria, hypertension, joint pains, rashes, etc

Abnormal C3, C4, ANA, dsDNA, anemia, thrombocytopenia, etc

IgA nephropathy:

IgA deposition in the mesangium, glomerular sclerosis, proliferative

changes, crescents in severe cases

Gross, intermittent, painless hematuria

No specific changes, although increased serum

IgA levels observed in some patients

Henoch-Schönlein purpura:

Same as IgA nephropathy

Purpura, joint pains, abdominal

pain, hematuria, etc

No specific laboratory data

Alport syndrome

Some thinning of basement membranes, " basket weave " changes in the

glomerular basement

membrane on electron microscopy

Sensorineural hearing loss, corneal abnormalities, hematuria, renal failure

No specific changes

Thin basement membrane disease

Average glomerular basement membranes reported to be 100-200 nm in children

in this condition

Persistent microscopic or gross hematuria, significant family history

No specific changes

Mesangiocapillary glomerulonephritis

Glomerular lobulations, thickening of the mesangial matrix and glomerular

basement membranes, crescents, etc

Hematuria, proteinuria, hypertension

C3 levels may be abnormal

Approach to hematuria

A comprehensive physical examination and a detailed history are

indispensable to the evaluation of hematuria. A urinalysis should be

obtained (as previously described), and a careful microscopic review of the

sample should be undertaken. A positive dipstick reaction should be followed

by a urine analysis to confirm the presence of RBCs and/or casts. The

absence of erythrocytes suggests myoglobinuria or hemoglobinuria, while the

absence of hemoglobin, red cells, or myoglobin should prompt a search for

other causes of red urine.

The next step in the differential diagnosis is localization of the bleeding.

The presence of red cell casts and preponderance of dysmorphic cells on

phase contrast microscopy are consistent with glomerular bleeding. Other

urine characteristics that help in distinguishing between glomerular and

nonglomerular hematuria are discussed in Phase contrast microscopy.

A urine culture should be obtained. Significant bacterial growth, indicative

of urinary tract infection or pyelonephritis, requires antibiotic treatment

and, possibly, further radiologic evaluation of the genitourinary tract for

obstruction, vesicoureteral reflux, cystic disease, and other abnormalities.

A urine culture showing " no growth " may need to be followed by imaging

studies. A urine sample should be sent for determination of the urine

calcium-creatinine ratio. An abnormal result should prompt a 24-hour urine

collection to confirm the diagnosis of hypercalciuria.

If hematuria is of glomerular origin, measurements of protein excretion and

serology tests may be in order. Low C3 levels should bring to mind

membranoproliferative glomerulonephritis or SLE as diagnostic possibilities.

The latter should be confirmed by measurements of ANA or dsDNA. A low C3

level in association with an elevated ASO titer or anti-DNAse B, are

indicative of poststreptococcal glomerulonephritis. The concomitant presence

of hematuria and proteinuria often indicates serious renal disease. A kidney

biopsy should be considered if proteinuria is persistent.

The approach to the evaluation of hematuria varies among physicians and no

single method applies in all circumstances. One approach is outlined in

Pictures 1-3.

TREATMENT

Medical Care:

Asymptomatic (isolated) hematuria generally does not require treatment. In

conditions associated with abnormal clinical, laboratory, or imaging

studies, treatment may be necessary, as appropriate, with the primary

diagnosis.

Surgical Care:

Surgical intervention may be necessary in certain anatomical abnormalities,

such as ureteropelvic junction obstruction or significant urolithiasis.

Consultations: Consultations are required in patients with urinary tract

anomalies and in some patients with systemic diseases (eg, bleeding

disorders, collagen vascular diseases, sickle cell nephropathy).

Diet:

Dietary modification usually is not indicated except for children who may

have a tendency to develop hypertension or edema as a result of their

primary disease process (eg, nephritis). In these patients, a low sodium

diet may be helpful. In addition, a diet containing the RDA for calcium plus

a low salt diet may be beneficial in children with hypercalciuria and

hematuria.

Activity: Activities of a child with asymptomatic, isolated hematuria should

not be restricted. However, these children and their parents should be

informed that strenuous exercise may aggravate hematuria. Restrictions in

physical activities may be indicated in children with severe hypertension or

cardiovascular disease.

Hematuria is a sign and not a disease. Therapy should be directed at the

process causing hematuria.

Further Outpatient Care:

Patients with persistent microscopic hematuria should be monitored at 6- to

12-month intervals for the appearance of signs or symptoms indicative of

progressive renal disease. Prominent among them are proteinuria,

hypertension, and a decrease in renal function.

Prognosis:

The prognosis of patients with asymptomatic isolated hematuria is good. The

ultimate prognosis for the various conditions associated with hematuria is

dependent on the primary medical condition that caused the hematuria in the

first place.

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