Pediatric Annals

Hematuria in Children

Ora Yadin, MD

Abstract

The detection of blood in a child's urine, whether accompanied by symptoms or asymptomatic, usually alarms the patient, the parents, and the physician. This concern often results in the performance of many laboratory tests, radiological examinations, and other procedures, some of which are unnecessary, causing the patient and family further distress, pain, and expense. The investigation of hematuria in a child must take into consideration the clinical presentation, the patient and family histories, and the physical examination so that a logical and orderly work-up can be undertaken. Ine pediatrician's responsibility is to ensure that serious, treatable, and progressive conditions are not overlooked, while avoiding the performance of unnecessary studies. When the initial work-up is negative, the pediatrician should be able to reassure the patient and parents and provide them with guidelines for further studies if and when such studies are indicated.

Although gross hematuria can be noticed by the child and the parents, the urine color may vary from bright red, to pink to "tea-color" brown, depending on the origin of the blood in the urinary tract, the urine concentration, and other factors. It is important to confirm the presence of blood by dipstick and microscopy in order to differentiate between true hematuria and possible presence of interfering compounds in the urine.

POSITIVEDIPSTICK

Not every red, pink, orange, or brown urine signals hematuria. Several foods, substances, and drugs may color the urine, the more common ones being beets, blackberries, lead, urates ("brick-dust diaper*), bile pigments, diphenylhydantoin, pyridium, rifampin, desferoxamine mesylate, phenothiazines, Phenolphthalein, Serratia marcescens infection, myoglobin, and hemoglobin. The dipsticks used for detection of blood in the urine are very sensitive in detecting intact red blood cells (RBCs) as well as minute amounts of free hemoglobin and myoglobin (0.02 and 0.03 mg/dL, respectively).1 All three produce a positive result on the dipstick, therefore making the microscopic examination of the urine an essential part of any urine analysis.

Table

PROGNOSIS

What is the prognosis of asymptomatic, isolated microscopic hematuria in a child? Some investigators of large series of children with isolated microscopic hematuria conclude that the prognosis is almost universally good,2,6 while others find that in 10% to 50% of these children the hematuria is an indicator of progressive renal disease.29'32 Many authors have attempted to differentiate benign hematuria from that leading to serious disease. Trachtman et al31 tried to identify the clinical characteristics that may enable recognition of children with an increased likelihood of having abnormal renal histology and found that the groups of patients with a positive family history of hematuria or any episodes of gross hematuria had a higher incidence of Alport's syndrome and IgA nephropathy on histology.

In a study conducted by Miller et al,30 100 children with recurrent gross hematuria or persistent microscopic hematuria underwent follow-up for a mean duration of 8.2 years. The authors found Alport's syndrome in 20% and IgA nephropathy in 26% of the biopsies examined. In some of these patients, however, the hematuria was accompanied by other findings and symptoms such as proteinuria, abdominal pain, arthralgia, or general malaise. Adverse prognostic features were persistence of microscopic hematuria, proteinuria at presentation, and significant changes on renal biopsy.

Schoeneman et al29 analyzed the clinical and histologic features of 55 children with persistent hematuria for at least 1 year, none of whom had any clinical findings that identified a glomerular disease of known clinical type. Two variables were found to be highly predictive of a poor prognosis: proteinuria > 1 g/day and the presence of interstitial fibrosis and foam cells on renal biopsy.

In a multicenter Hungarian study conducted by Turi et al,32 341 children…

The detection of blood in a child's urine, whether accompanied by symptoms or asymptomatic, usually alarms the patient, the parents, and the physician. This concern often results in the performance of many laboratory tests, radiological examinations, and other procedures, some of which are unnecessary, causing the patient and family further distress, pain, and expense. The investigation of hematuria in a child must take into consideration the clinical presentation, the patient and family histories, and the physical examination so that a logical and orderly work-up can be undertaken. Ine pediatrician's responsibility is to ensure that serious, treatable, and progressive conditions are not overlooked, while avoiding the performance of unnecessary studies. When the initial work-up is negative, the pediatrician should be able to reassure the patient and parents and provide them with guidelines for further studies if and when such studies are indicated.

Although gross hematuria can be noticed by the child and the parents, the urine color may vary from bright red, to pink to "tea-color" brown, depending on the origin of the blood in the urinary tract, the urine concentration, and other factors. It is important to confirm the presence of blood by dipstick and microscopy in order to differentiate between true hematuria and possible presence of interfering compounds in the urine.

POSITIVEDIPSTICK

Not every red, pink, orange, or brown urine signals hematuria. Several foods, substances, and drugs may color the urine, the more common ones being beets, blackberries, lead, urates ("brick-dust diaper*), bile pigments, diphenylhydantoin, pyridium, rifampin, desferoxamine mesylate, phenothiazines, Phenolphthalein, Serratia marcescens infection, myoglobin, and hemoglobin. The dipsticks used for detection of blood in the urine are very sensitive in detecting intact red blood cells (RBCs) as well as minute amounts of free hemoglobin and myoglobin (0.02 and 0.03 mg/dL, respectively).1 All three produce a positive result on the dipstick, therefore making the microscopic examination of the urine an essential part of any urine analysis.

Table

TABLEIClues to Localization of Hematuria

TABLEI

Clues to Localization of Hematuria

Hemoglobinuria without hematuria results from excess free hemoglobin in the blood and can be seen in any condition causing hemolysis. Myoglobinuria without hematuria is seen following muscular damage such as trauma, convulsions, heat stroke, electric shock, myocardial infarction, prolonged strenuous exercise, and other conditions. Causes of falsepositive dipstick reactions include oxidizing contami' nants such as bacterial peroxidases from a urinary tract infection, a delay in reading the dipstick, and interfering compounds such as beets or aniline dyes. A false-negative result can occur in urines with a high-specific gravity and in urine containing large amounts of a reducing agent such as ascorbic acid.

DEFINITION

Hematuria is the presence of blood in the urine. It can present as macrohematuria or "gross hematuria," when the blood in the urine is evident to the naked eye, or as microscopic hematuria, when the urine looks clear but blood can be detected by a dipstick and RBCs can be seen when the urine is examined under the microscope. Microscopic hematuria may be accompanied by other signs and symptoms or may be completely asymptomatic with the blood discovered incidentally

The definition of microscopic hematuria is somewhat arbitrary Most authors require the detection of RBCs in sequential urine samples (two out of three) over a week to a few weeks before diagnosing microscopic hematuria.2 Careful preparation of the urine samples for the microscopic examination improves accuracy when comparing results from separate specimens. Ten to 15 mL of freshly voided urine should be centrifuged at 1500 rpm for 5 to 7 minutes, the supernatant carefully poured ofij and the sediment examined under high power magnification. Five to 10 high-power fields (HPFs) should be scanned to determine the "average" number of RBCs present per HPF. Another method for quantifying hematuria is with a "spot" quantitative count (number of RBCs per mL) on a centrifuged specimen.3 The presence of 5 to 10 erythrocytes per HPF in a centrifuged specimen is considered significant by a number of authors2,4; this roughly correlates with an erythrocyte concentration of between 100 and 800 per mL.

Macroscopic hematuria, also termed "gross hematuria," is blood in the urine seen with the naked eye. It can be persistent or recurrent, with microhematuria present or not between episodes of gross hematuria.

PREVALENCE

The frequency of gross hematuria in a busy pediatric emergency walk- in clinic during 24 consecutive months was found to occur in 0.13% of visits.5 There was no sex predilection in the total population; however, females predominated among both documented and suspected urinary tract infections, while patients with recurrent gross hematuria, trauma, or meatal stenosis were primarily males.

The prevalence of microscopic hematuria in children depends on whether asymptomatic populations are screened routinely and on the definition used. In a large study of 12 000 school-aged children, 6% were found to have >5 RBC/HPF in a single urine specimen; however, only half of those had ^5 RBC/ HPF in a second or third urine specimen collected within 7 days.2 Hematuria was significantly more prevalent in girls in that study. The annual incidence of new cases, defined as ^5 RBC/HPF for boys and girls 6 to 12 years of age, was 0.4%.

In another study of an unselected population of almost 9000 children 8 to 16 years of age, microscopic hematuria was found in one or more specimens in 4.1%, and in two or more specimens in 1.1% of the children. However, in fewer than 0.5% the hematuria persisted longer than 6 months.6 The prevalence was not age- or sex-dependent in this study.

The American Academy of Pediatrics has recommended routine urinalysis as a component of well child care,7 whereas a more recent study found urinalysis of little value as a routine admission test in hospitalized patients.8

LOCALIZATION OF HEMATURIA

Hematuria can originate from any part of the urinary tract. Localizing the source of the bleeding to the kidney or the lower urinary tract can facilitate the work-up and assist the pediatrician in developing the most efficient diagnostic plan. It is not always possible to determine the origin of the hematuria from the outset, although some accompanying findings can provide clues to differentiating glomerular from nonglomerular bleeding (Table 1 ).

The presence of RBC casts in the urine usually indicates a glomerular origin (their absence, however, does not always rule out glomerular disease); The presence of other cellular casts and renal tubular cells also points to a glomerular cause of bleeding. Proteinuria may be present regardless of the cause of bleeding, but proteinuria testing 2+ (100 mg/dL) or greater on the dipstick suggests a glomerular source. Gross hematuria usually obscures an accurate reading of die dipstick for protein concentration above 2 + . In such situations, a timed urine collection for quantifying the proteinuria might be necessary. A brownish "tea-colored" or "colacolored" urine usually indicates the bleeding is glomerular, whereas lower tract bleeding colors the urine red or pink. Passing blood clots in the urine usually points to the bladder or ureters as the source of the bleeding.

Determining the morphology of the urinary erythrocytes using phase-contrast microscopy has been suggested as a simple way of differentiating glomerular from lower tract bleeding.9,10 Erythrocytes that are deformed ("dysmorphic") or pitted are likely to be glomerular in origin, whereas those that are normal and uniform in shape, resembling normal circulating blood cells, are likely to originate from the lower urinary tract. The usefulness of this technique, however, depends on the experience of the laboratory as well as the criteria used for the definition of dysmorphic erythrocytes and the percentage of abnormal erythrocytes required for the diagnosis of glomerular bleeding.11

A more recently described technique that can help in identifying the source of hematuria is a urinary erythrocyte volume analysis by an electronic Coulter counter. 1Z,!3 However, mixed volume distribution patterns were found in 38% of patients with nonglomerular hematuria due to the presence of small fragmented cells, crystals, or other urinary contaminants.1.3 Table I summarizes the clues to differentiating between glomerular and nonglomerular hematuria.

ETIOLOGIES OF HEMATURIA

Some of the possible causes of microscopic hematuria in children are listed in Table 2. Some of these are more common in children and others are less common, while some are extremely rare. The pediatrician therefore should attempt a logical and stepwise work-up of a child with microscopic hematuria, taking into account pertinent patient history, family history, and accompanying findings.

INITIAL EVALUATION

Once the presence of hematuria has been confirmed, the evaluation should begin with a detailed history and careful physical examination. The history taking should be thorough, inquiring about strenuous exercise, recent trauma, recent bladder catheterization, habits (masturbation, excessive bicycle riding, or urethral foreign body insertions), menstruation, symptoms of urinary tract infection, recent or past symptoms of renal colic or passage of a stone in the urine, and any recent infections, particularly a throat, skin, or upper respiratory infection. Recent or present rashes, joint complaints, fevers, and recent or present bloody diarrhea should be inquired about, as should ingestion of certain medications including antibiotics, which can cause interstitial nephritis, and cyclophosphamide, which can cause hemorrhagic cystitis. In a baby or infant, the history should include questions about birth asphyxia and catheterization of umbilical vessels.

Table

TABLE 2Causes off Microscopic Hematuria In Children

TABLE 2

Causes off Microscopic Hematuria In Children

A family history should include questions about hematuria or proteinuria in family members or other relatives, deafness or a hearing deficit (Alport's syndrome), renal failure or need for dialysis and kidney transplantation in any relative (ie, Alport's syndrome, systemic lupus erythematosus [SLE], or chronic glomerulonephritis), hypertension (ie, polycystic kidney disease, acute glomerulonephritis, or renal failure), urolithiasis (ie, stones or hypercalciuria), sickle cell anemia, and hemophilia or other coagulation factor deficiency.

A complete physical examination should be performed, looking for findings that might be helpful in diagnosing one of the causes of hematuria outlined in Table 2. Measuring the blood pressure in a child with hematuria is essential. The presence or absence of hypertension helps to decide how extensive the workup should be. If blood pressure is elevated for age, the hematuria requires a more intensive diagnostic evaluation. The child's height and weight should be measured carefully and plotted on an appropriate growth chart. A marked failure to thrive or even a trend of felling away from the previous growth pattern might indicate a chronic renal insufficiency or long-standing acidosis.

The eyes should be examined for evidence of acute or long-standing hypertension, abnormalities of the lens (lenticonus in Alport's syndrome), or deposits that may be present in certain metabolic diseases. The presence of costovertebral angle tenderness may indicate a urinary tract infection. Bruises on the flanks or abdomen can indicate recent trauma. The abdomen should be palpated carefully. An abdominal mass found in an infant with hematuria requires a prompt investigation for Wilms' tumor. An abdominal mass also can be caused by poly- or multicystic kidneys, hydronephrosis, and ureteropelvic junction obstruction. Pallor might be a sign of anemia from chronic renal insufficiency, hemolytic-uremic syndrome, hemoglobinopathy, leukemia, or tumors.

Rashes and arthritis can occur in HenochSchönlein purpura and SLE. Edema might suggest acute glomerulonephritis or one of the causes of the nephrotic syndrome. The genitalia should be included in the physical examination of a child with hematuria to rule out any tears and abrasions that might be the result of sexual molestation or trauma; vaginal or penile discharge might accompany a vaginal or urethral infection or a foreign body.

INITIAL LABORATORY STUDIES

The urine should be examined microscopically looking for RBC casts, and a test for proteinuria should be done. When possible, determination of the red blood cells morphology (phase-contrast microscopy) can be helpful in localization of the hematuria. A urine culture should be sent initially since a third of urinary tract infections are associated with hematuria, and other signs and symptoms of such infections may be minimal or overlooked. Also, urinary tract infection is the most common cause of macroscopic hematuria.5

Viruses are not often considered as a cause of urinary tract infection, but an important cause of hematuria is acute hemorrhagic cystitis particularly associated with adenovirus types 11 and 21, which cause a short, self-limiting disease characterized by hematuria and symptoms of bladder inflammation.14 Idiopathic hypercalciuria has been associated with otherwise unexplained hematuria in 28% to 35% of children referred for evaluation of hematuria.15·16 This condition precedes overt urolithiasis by 1 to 6 years in several studies.15'18 Idiopathic hypercalciuria may be the result of primary intestinal nyperabsorption of calcium (absorptive hypercalciuria) or impaired renal tubular reabsorption of calcium (renal hypercalciuria). Calcium excretion measured after oral calcium loading and after dietary abstinence from milk products and supplemental vitamins for at least 5 days can help to differentiate between the two causes of hypercalciuria.15,16,19

Hypercalciuria has been defined as urinary calcium excretion of >4 mg/kg/day16,20,21 or a calcium to creatinine ratio (Ca/Cr) in an untimed random urine specimen of >0.22.22 In a study from 1984, which established reference values for urinary calcium excretion in healthy children aged 6 to 18 years, the Ca/Cr ratios were independent of age and sex.22 In a more recent study, however, the normal values for Ca/Cr were age related and were found to be much higher in infants than in older children and adults. The 95th percentile for Ca/Cr for infants younger than 7 months of age was 0.86; for infants 7 to 18 months, 0.6; for children 19 months to 6 years, 0.42; and for adults, 0.22. No significant changes in the mean Ca/Cr were noted during week-long periods of calcium supplementation of infant formula.23 Because hypercalciuria is found so frequently during the evaluation of children with hematuria, it is reasonable to send a random urine sample for Ca/Cr in the initial work-up.

Sickle cell disease and sickle cell trait most commonly give rise to gross hematuria but also can cause microscopic hematuria; therefore, a sickle cell screen should be sent in a child being evaluated for hematuria who is at risk for sickle cell disease. Tests of renal function in an otherwise well child with hematuria are likely to be normal and usually nothing more than serum creatinine and blood urea nitrogen (BUN) levels are required in this initial phase of the work-up. A complete blood cell count (CBC) and a platelet count will complete the initial laboratory evaluation. It is worth checking the urine of first-degree relatives of the patient for hematuria not only to detect severe forms of familial nephritis such as Alport's syndrome, but also because some forms of relatively benign hematuria have a familial tendency. Although a renal ultrasonographic test is relatively costly, obtaining one should be considered at this stage of the evaluation because the procedure is noninvasive and provides information about the presence or absence of stones, hydronephrosis, structural anomalies of the kidneys and the urinary tract, renal dysplasia, renal vein thrombosis, and most importantly, about the presence or absence of tumors of the kidneys. Some pediatricians and urologists continue to favor intravenous urography as an imaging method to evaluate the presence or absence of structural and functional renal parenchymal injury. However, in experienced hands, renal ultrasonography is as reliable as intravenous urography for excluding gross lesions. The value provided by a normal renal ultrasound in terms of reassurance to the anxious parents justifies its cost.

PHASE II WORK-UP

In phase Il of the work-up, some of the less common causes of hematuria in children are sought, such as different glomerulopathies, coagulation problems, and some of the anatomical and vascular abnormalities.

Abnormally low complement levels can be found in acute postinfectious glomerulonephritis (APIGN), SLE, membranoproliferative glomerulonephritis (MPGN), and in some other glomerulonephritides. The diagnosis of acute post-streptococcal glomerulonephritis requires evidence of streptococcal infection demonstrated by elevated streptococcal antibody titers (ASO and antiDNAse B). The acute phase of the disease usually lasts for I to 2 weeks, but the hematuria may persist for months. The complement levels, which are low during the acute phase, usually return to normal within 6 to 8 weeks.24 Rarely, renal involvement with hematuria may be the only manifestation of SLE, so a test for antinuclear antibodies should be obtained. Membranoproliferative glomerulonephritis is a chronic disease, and many children will progress to end-stage renal failure. Membranoproliferative glomerulonephritis usually presents with the nephrotic syndrome; however, microscopic hematuria also is very common.25

The hypocomplementemia associated with this type of glomerulonephritis, especially of C3, persists in contrast to the usual return to normal levels seen in APIGN. Glomerulonephritis abo may be associated with several forms of chronic infection such as bacterial endocarditis, infected ventriculoatrial or ventriculoperitoneal shunts, malaria, hepatitis, and mononucleosis. Although in most cases the diagnosis of these conditions will be suggested by the clinical picture, they may present with only hematuria or a nephritic-type urine. Hypocomplementemia is common, and treatment of the underlying infection usually results in resolution of the glomerulonephritis and return of the complement to normal levels.

The glomerulonephritis associated with vasculitis (Wegener's granulomatosis, periarteritis nodosa, and pauci-immune glomerulonephritis) or with antibodies directed against the glomerular basement membrane (anti-glomerular basement membrane [GBM] disease and Goodpasture's syndrome) generally produce severe, rapidly progressive glomerulonephritis with or without lung involvement. However, rarely, they can present initially with hematuria only. Anti-GBM antibody levels are helpful in the diagnosis of antiGBM disease, and anti-neutrophil cytoplasmic antibodies (ANCA) are sensitive markers of active crescentic glomerulonephritis.

An audiogram to test for a high-frequency hearing deficit should be obtained even with a negative family history for Alport's syndrome because of a high spontaneous mutation rate that occurs in this syndrome.

Tuberculosis is a rare cause of childhood hematuria in western countries. However, with the increasing incidence of tuberculosis in recent years, it should be considered in a child with a history of exposure and leukocyturia with no bacterial growth on a urine culture.

At this point in the work-up, if no etiology for the hematuria has been discovered, in the absence of proteinuria, RBC casts, hypertension, or renal insufficiency, and in face of a normal renal ultrasound, it is reasonable to defer further investigations in an asymptomatic child with microscopic hematuria. The parents and patient should be reassured that life-threatening conditions have been ruled out and that additional studies will be undertaken if new findings develop or if the hematuria persists. It is imperative to explain to the family that the patient must be evaluated periodically with urinalyses (including a dipstick for protein), blood pressure measurements, and kidney function tests until the hematuria resolves or new findings appear that warrant additional evaluation.

ADVANCED WORK-UP

In cases where there is a questionable history of trauma or a past urinary tract infection that was not investigated radiologically, the physician should consider obtaining an imaging study such as a voiding cystourethrogram (VCUG) to rule out reflux or abnormalities of the bladder or urethra, an intravenous pyelography to better determine the anatomy of the kidneys and ureters, or an abdominal computed tomography scan to diagnose renal injury. A renal scan is obtained to confirm the presence of a ureteropelvic junction obstruction or when a parenchymal scar is suspected.

The nutcracker syndrome is a rare vascular abnormality with compression of the left renal vein between the superior mesenteric artery and the aorta, causing venous hypertension and formation of ureteral and renal pelvic venous varicosities.26 Hematuria can be a presenting finding of this syndrome, although the underlying pathophysiology is not yet completely understood. Magnetic resonance imaging is the imaging modality that has been the most rewarding in the diagnosis of this syndrome.26

Cystoscopy is rarely indicated in the work-up of a child with hematuria. Evidence of bladder or urethral filling defects on the VCUG in a child with gross or microscopic hematuria might indicate the presence of a mass such as a stone, polyp, or rumor and may require cystoscopy for diagnostic and therapeutic purposes. Some boys with gross hematuria, dysuria, and sterile urine cultures who underwent cystoscopy were found to have hemorrhagic urethritis, probably the result of local trauma.27

A kidney biopsy should be considered if treatable, progressive or hereditary glomerular disease is suspected in order to allow the physician to discuss treatment options with the patient and parents, or if there is no treatment, to offer the family genetic counseling. The biopsy must be done by an experienced specialist in a setting equipped with facilities for dealing with any complication that might occur during or after the procedure. Expert processing and interpretation of the biopsy sample are mandatory. Indications for performing a renal biopsy include coexistent significant proteinuria (>2 + on the dipstick), persistent hypocomplementemia, a family history of nephritis, hematuria with hearing deficit, renal insufficiency suggestive of a hereditary nephritis, decreased renal function, hypertension when polycystic kidneys and other anatomical or vascular abnormalities have been ruled out, recurrent episodes of gross hematuria that are not explained by a nonglomerular cause, long-standing persistent microscopic hematuria (>1 year), and extreme parental anxiety with insistence on knowing a specific diagnosis.

The work-up of a patient with gross hematuria is more likely to yield a specific diagnosis than is the work-up of a patient with asymptomatic microscopic hematuria. Several studies have reported a diagnostic yield of 50% to 75%.4·5·28 In one study of 158 patients with gross hematuria seen in an unselected pediatric emergency walk-in clinic during 24 months, 58% had readily apparent causes for gross hematuria such as urinary tract infection, perineal irritation, meatal stenosis with ulcer, trauma, a prior surgical procedure, coagulopathy, and stones. Of the remaining 42%, six patients had acute glomerulonephritis and seven patients had a history and course over a 2-year follow-up period compatible with "benign recurrent hematuria," although none had a renal biopsy. Other diagnoses included ureteropelvic junction obstruction, cystitis and suspected urinary tract infection, epididymitis, and Wilms' tumor. Only 13 patients had no discernible cause for their gross hematuria.5

When should the primary physician refer a child with hematuria to a pediatric nephrologist? The answer depends on the availability to the physician of laboratory and radiological facilities necessary to proceed with the evaluation, on the physician's level of comfort in working up such a patient, and on nie findings encountered during the work-up. Often, the nephrologist is needed only to reassure the family that dangerous and treatable conditions already have been ruled out by the work-up done by the primary physician. It is advisable to refer a child with gross hematuria to a pediatric nephrologist or when the physician learns about a family history of glomerulonephritis, nerve deafness, chronic renal failure and end-stage renal disease, familial hematuria, coexistent significant proteinuria, hypertension, abnormal kidney function tests, persistent hypocomplementemia, findings suggesting a systemic disease (fever, arthritis or arthralgia, and skin rash), and when parental anxiety seems unduly high. Finally, the nephrologist can help to explain the indications for and risks of a kidney biopsy. The suggested stepwise work-up of a child with hematuria is outlined in Table 3.

Table

TABLE 3Stepwise Work-Up of a Child With Hematuria

TABLE 3

Stepwise Work-Up of a Child With Hematuria

PROGNOSIS

What is the prognosis of asymptomatic, isolated microscopic hematuria in a child? Some investigators of large series of children with isolated microscopic hematuria conclude that the prognosis is almost universally good,2,6 while others find that in 10% to 50% of these children the hematuria is an indicator of progressive renal disease.29'32 Many authors have attempted to differentiate benign hematuria from that leading to serious disease. Trachtman et al31 tried to identify the clinical characteristics that may enable recognition of children with an increased likelihood of having abnormal renal histology and found that the groups of patients with a positive family history of hematuria or any episodes of gross hematuria had a higher incidence of Alport's syndrome and IgA nephropathy on histology.

In a study conducted by Miller et al,30 100 children with recurrent gross hematuria or persistent microscopic hematuria underwent follow-up for a mean duration of 8.2 years. The authors found Alport's syndrome in 20% and IgA nephropathy in 26% of the biopsies examined. In some of these patients, however, the hematuria was accompanied by other findings and symptoms such as proteinuria, abdominal pain, arthralgia, or general malaise. Adverse prognostic features were persistence of microscopic hematuria, proteinuria at presentation, and significant changes on renal biopsy.

Schoeneman et al29 analyzed the clinical and histologic features of 55 children with persistent hematuria for at least 1 year, none of whom had any clinical findings that identified a glomerular disease of known clinical type. Two variables were found to be highly predictive of a poor prognosis: proteinuria > 1 g/day and the presence of interstitial fibrosis and foam cells on renal biopsy.

In a multicenter Hungarian study conducted by Turi et al,32 341 children with isolated microscopic hematuria,, persistent for at least 6 months at the beginning of observation, underwent long-term follow-up. Twenty percent had hypercalciuria, and in 72% of these, urolithiasis developed 2 to 15 years following presentation. None of these patients developed hypertension or decreased creatinine clearance. Proteinuria appeared more than 2 years after presentation with the degree of proteinuria progressively increasing with time in 13.8% of the children, between the third and fifth years in 8.6%, and after the fifth year in 37%. In 47 children in whom proteinuria was associated with hematuria 2 to 17 years after initial presentation, histological examination showed a more serious glomerulopathy. Azotemia developed in 36 children; in 23 of these, the creatinine clearance decreased 2 to 5 years after the appearance of hematuria. These authors concluded that the final outcome of persistent/recurrent hematuria may be predictable only after long-term follow-up and that persistent microhematuria in the beginning (with or without episodes of gross hematuria) and associated proteinuria or hypertension suggest a worse prognosis.

Another study of biopsies from 65 children with isolated hematuria for at least 1 year (with no associated proteinuria, hypercalciuria, or hypertension) found variable histologic abnormalities in 62 of the biopsies.33 Thirty-three of the children with histologic abnormalities were classified as having "benign hematuria" with thinning of the glomerular basement membranes seen on the electron microscopy. The hematuria was familial in 23 of these children (70%) with what seemed to be a dominant inheritance pattern. Serum creatinine was normal in all of them, and there was no associated proteinuria. However, 29 children in this study did have more serious forms of glomerulopathy, such as 8 with Alport's nephropathy, 16 with IgA nephropathy, and 5 with increased mesangial cellularity.

Yoshikawa et al34 systematically searched for the entity of "thin membrane nephropathy" among biopsy specimens from 218 children with a wide range of presenting illness, including 31 with a family history suggestive of benign familial hematuria. Widespread thinning of the glomerular basement membrane affecting more than 50% of glomerular capillary loops was found in 20 patients. All had persistent microscopic hematuria without proteinuria, and one also had an episode of macroscopic hematuria. Measurements of the glomerular basement membrane thickness were in the range of 211 nm to 267 nm (versus 300 nm in patients with minimal change nephrotic syndrome). Half of the 20 children had a family history of benign hematuria, but did not differ in any other way from those who did not. Hematuria continued in all of the patients during follow-up of 1 to 8 years, but there were no other manifestations of renal disease.

Another review of 130 children with persistent microhematuria revealed that the most common abnormality was a familial thinning of the glomerular basement membrane.35 When followed for up to 13 years, all patients with this entity continued to have microscopic hematuria, but showed no deterioration of renal function. The medium-term prognosis of this condition seems to be excellent; however, there have been reports of adult patients with diffuse thinning of the glomerular basement membrane as their histological lesion, who also had proteinuria, hypertension, and a degree of renal insufficiency,36 so it seems possible that some patients with thin membrane nephropathy may go on to progressive renal disease.

Thus, although the generally accepted rule that a child with hematuria and associated proteinuria should undergo a work-up for a glomerular disease still holds true, there are no absolute prognostic indicators to help the physician recognize the children who might develop a progressive renal disease later on. Therefore, it is imperative to continue to carefully evaluate children with persistent hematuria for several years, checking for the appearance of proteinuria, hypertension, or renal function impairment.

SUXiMARY

A work-up of a child with suspected hematuria should be undertaken once the primary physician has determined that there actually are red blood cells in the urine and that the hematuria is persistent. Evaluation of a child with persistent microscopic hematuria is facilitated with the determination of whether the blood originates from the glomeruli or whether it comes from elsewhere in the urinary tract. Clues to a glomerular origin include the presence of other manifestations of glomerular disease such as significant proteinuria, RBC casts, and dysmorphic erythrocytes in the urinary sediment, hypertension, and renal insufficiency. Clues to the blood originating from the lower urinary tract include blood clots in the urine, normal erythrocyte morphology, and a pertinent history pointing to the lower tract such as that of trauma, urolithiasis, urological or vascular abnormality, or symptoms of bladder inflammation.

The initial evaluation should include a detailed patient history and family history as well as a careful physical examination looking for clues to the presence of a familial, hereditary, or chronic kidney disease. A logical, stepwise initial work-up should follow with the goal of ruling out life-threatening and treatable diseases. If there are no indications for immediate further intervention and the cause of the hematuria remains unclear after the initial work-up has been completed, the parents and patient should be reassured that there are no life-threatening conditions and that although the etiology of the blood in the urine is yet unknown, there is time to follow the patient and plan for additional studies if and when they are indicated.

The family's concerns (ie, "Is this cancer?," "Will my child require dialysis and transplantation?") should be addressed frankly, and the physician should mention those diagnoses that may lead to renal failure, but have not been absolutely ruled out yet before a kidney biopsy has been performed, such as Alport's syndrome and IgA nephropathy. The child with isolated microhematuria should be evaluated regularly with urinalyses looking for persistence of the hematuria and appearance of proteinuria, blood pressure measurements, and renal function tests. If the microhematuria persists for 6 to 12 months, a kidney biopsy should be considered. Primary care pediatricians should refer children with hematuria to a pediatric nephrologist if they are unable to proceed with the work-up at any point due to lack of necessary laboratory or radiologic facilities, when there is a family history of a chronic renal disease, coexistent significant proteinuria, hypocomplementemia, or findings suggestive of a systemic disease. Frequently, the pediatric nephrologist's assistance is needed merely to reassure the family that the appropriate work-up has been performed or to explain the indications and technicalities of a kidney biopsy.

Although many reports say that the prognosis of asymptomatic isolated hematuria in children is universally good, others have found that 10% to 50% of children with persistent hematuria will eventually develop progressive chronic renal disease. No absolute prognostic indicators have been identified; therefore, it is important to continue to evaluate these patients, sometimes for many years.

REFERENCES

1. Ripper S. Asymptomatic proteinuria. Postgrad Med. 1977;62: 125-1 30.

2. Dodge WF, West EF, Smith EH, Bunce H III. Proteinuria and hematuria in school children: epidemiology and early natural history. J Pediatr. 1976;88:327-347.

3. Kesson AM, Talbort JM, Gyory AZ. Microscopic examination of urine. Lancet. 1978;2:809-812.

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TABLEI

Clues to Localization of Hematuria

TABLE 2

Causes off Microscopic Hematuria In Children

TABLE 3

Stepwise Work-Up of a Child With Hematuria

10.3928/0090-4481-19940901-06

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