Hematuria

Hematuria is one of the most common urinary findings that result in children presenting to pediatric nephrologists. Generally, hematuria is defined as the presence of 5 or more 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.

Hematuria should be confirmed by the demonstration of blood on screening urinalysis or by direct visualization with urine microscopy. Commercially available urine dipstick screening tests are very sensitive for the presence of heme protein in urine.

Because urine dipstick screening tests are highly sensitive, pediatricians should be aware of the many common causes of false-positive urinalysis results for blood. In patients with rhabdomyolysis, the presence of myoglobin in the urine, which is a structurally similar pigment protein, can result in a false-positive dipstick test for blood without true hematuria. Heme-positive urinalyses that are negative for blood on microscopy can also be caused by intravascular hemolysis, as well as contamination with povidone-iodine or other oxidizing substances. In addition, excluding discoloration of the urine from the ingestion of various foods (eg, beets, rhubarb, and blackberries) or medications (eg, rifampicin, nitrofurantoin, and metronidazole) is important.

In contrast, false-negative dipstick tests despite the presence of hematuria could result from dilute urine specimens, highly acidic urine pH (< 5), and the presence of reducing substances (such as ascorbic acid).[1]

The role of the primary care pediatrician in the management of a child with hematuria includes the following:

• Recognize and confirm the finding of hematuria.

• Initiate a preliminary diagnostic workup to try to identify common etiologies.

• Select patients who have significant urinary system disease that might require further referral for diagnosis or management.

The etiology and pathophysiology of hematuria vary. For instance, hematuria of glomerular origin may be the result of a structural disruption in the integrity of the glomerular basement membrane caused by inflammatory or immunologic processes.[3] Chemicals may cause toxic disruptions of the renal tubules, whereas calculi may cause mechanical erosion of mucosal surfaces in the genitourinary tract, resulting in hematuria.

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 glomerular hematuria in children include the following:

• Thin basement membrane disease (benign familial hematuria)

• Alport syndrome

• Immunoglobulin A (IgA) nephropathy

• Hemolytic-uremic syndrome

• Postinfectious glomerulonephritis

• Membranoproliferative glomerulonephritis

• Lupus nephritis

• Anaphylactoid purpura (Henoch-Schönlein purpura)

Potential causes of nonglomerular hematuria in children include the following:

• Fever

• Strenuous exercise

• Mechanical trauma (masturbation)

• Menstruation

• Foreign bodies

• Urinary tract infection

• Hypercalciuria/urolithiasis

• Sickle cell disease/trait

• Coagulopathy

• Tumors: Urothelial papilloma

• Drugs/toxins (nonsteroidal anti-inflammatory drugs [NSAIDs], anticoagulants, cyclophosphamide, ritonavir, indinavir)

• Anatomic abnormalities (hydronephrosis, polycystic kidney disease, vascular malformations)

• Hyperuricosuria

United States data

The prevalence of gross hematuria in children is estimated to be 0.13%. In more than half of the cases (56%), this is due to an easily identifiable cause. The most common cause appears to be cystitis (20-25%). Asymptomatic microscopic hematuria is, on average, 10-fold as prevalent as gross hematuria (1.5%, range 0.4-4.1%, depending on the criteria used to define hematuria). With repeated evaluations, the prevalence of asymptomatic microscopic hematuria decreases to less than 0.5%, supporting the notion that most cases of hematuria in children are transient.[1]

The incidence of simultaneous hematuria and proteinuria is estimated to be only 0.06%, but their coexistence signals significant renal disease. Hematuria or proteinuria that persists on repeated investigations warrants additional evaluation.[4]

Race-, sex-, and age-related demographics

The incidence of hematuria in specific racial groups is determined by the primary cause. For example, idiopathic hypercalciuria is infrequent in black and Asian children but relatively common in whites. Conversely, hematuria caused by sickle cell disease is more common in blacks and Hispanics than in whites.

Sex may predispose a child to specific diseases that manifest as hematuria. For example, the sex-linked form of Alport syndrome has a male preponderance, whereas lupus nephritis tend to be more common in adolescent girls.

Prevalence of certain conditions varies with age.[3]  For instance, Wilms tumors are more frequent in children of preschool age, whereas acute postinfectious glomerulonephritis is more frequent in the school-aged population. In adults, hematuria is often a sign of malignancy of the genitourinary tract (eg, renal cell carcinoma, bladder tumors, prostatic tumors). These conditions are rare in children.

Morbidity/mortality

In general, children with isolated asymptomatic microscopic hematuria tend to do well, whereas those with associated findings (eg, hypertension, proteinuria, abnormal serum creatinine levels) are more likely to have serious problems. Because hematuria is the end result of various processes, the morbidity and mortality rates of the condition depend on the primary process that initiated it.

Inform children and their parents that strenuous exercise may aggravate hematuria; however, hematuria by itself should not prevent the child from participating in sports. Despite the sometimes alarming intensity or persistence of hematuria, parents must be informed that, by itself, hematuria rarely causes anemia.

For helpful patient education resources, see the article Blood in Urine (Hematuria).

The first step in the evaluation of hematuria is a detailed review of the history and a thorough physical examination.

The presence or absence of hypertension or proteinuria helps to decide how extensively to pursue the diagnostic evaluation. The initial evaluation should be directed toward important and potentially life-threatening causes of hematuria in any child who has any of the following in addition to hematuria: hypertension, edema oliguria, significant proteinuria (more than 500 mg per 24 hours), or RBC casts. An attempt should be made to distinguish glomerular causes of hematuria from extraglomerular ones, as this helps in prioritizing the investigations.

• A history of passage of clots in urine suggests an extraglomerular cause of hematuria.

• 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 early-morning periorbital puffiness, weight gain, oliguria, the presence of dark-colored urine, and the presence of edema or hypertension suggests a glomerular cause.

• Hematuria due to glomerular causes is painless.

• A history of a recent throat or skin infection may suggest postinfectious glomerulonephritis.

• A history of joint pains, skin rashes, and prolonged fever in adolescents suggests a collagen vascular disorder.

• The presence of anemia cannot be accounted for by hematuria alone, and, in a patient with hematuria and pallor, other conditions such as systemic lupus erythematosus and bleeding diathesis should be considered.[5]

• Skin rashes and arthritis can occur in Henoch-Schönlein purpura and systemic lupus erythematosus.

• Information regarding exercise, menstruation, recent bladder catheterization, intake of certain drugs or toxic substances, or passage of a calculus may also assist in the differential diagnoses.

• Because certain diseases that present with hematuria are inherited or familial, asking for a family history that is suggestive of Alport syndrome, collagen vascular diseases, urolithiasis, or polycystic kidney disease is important.

In the general physical examination, the most important step is to measure the blood pressure (with an appropriate-sized cuff) and evaluate for the presence of periorbital puffiness or peripheral edema.[6, 7]

• A detailed skin examination is necessary to look for purpura.

• An abdominal examination is indicated to look for palpable kidneys (Wilms tumor or hydronephrotic kidneys).

• A careful examination of the genitalia is also important.

• A detailed ophthalmological evaluation is helpful in familial hematurias.

The laboratory tests ordered for the evaluation of hematuria must be based on the clinical history and the physical examination. Identification of a glomerular and extraglomerular etiology of hematuria based on a good history and urine examination can help the physician to avoid requesting tests that may be unnecessary.

Urinalysis

Confirming that a child with red-colored urine has hematuria is mandatory. Dip strip analysis is critically important in patients with dark or abnormal-appearing urine because several substances may discolor the urine and give the appearance of hematuria. 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). Briefly dip the strip in the urine, tap off excess urine, and read the strip at the recommended time (usually 1 min). Dipsticks have a sensitivity of 100% and a specificity of 99% in detecting 1-5 RBCs per high-power field (hpf).

The presence of hematuria is most important to confirm, since both normal and abnormal causes (eg, hemoglobinuria, myoglobinuria) can produce false-positive results. Confirmation requires a microscopic examination of the urine for the presence of RBCs and casts. A freshly voided urine specimen should be used. 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. The urine sample is then carefully examined under high-power magnification. All noncellular and cellular elements should be noted and recorded. More than 5 RBCs per hpf is generally considered abnormal. RBC casts indicate a glomerulotubular source of hematuria. The absence of RBCs and RBC casts despite a positive dipstick test suggests 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 may also be seen.

Parents of children with isolated microscopic hematuria should be reassured that sufficient time remains to plan a stepwise evaluation. Other investigations should be avoided, and the dipstick and microscopic urinalysis should be repeated twice within 2 weeks.

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. Phase contrast microscopy 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.

Other laboratory studies

Elevated levels of BUN and creatinine suggest significant renal disease as the cause of hematuria.

CBC counts and, sometimes, platelet counts may be performed in selected patients with a clear history of a bleeding disorder. In general, coagulation studies and CBC counts 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.

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.

Measuring serum complement levels is important if a glomerular cause of hematuria is suspected. Low serum complement levels are seen in postinfectious glomerulonephritis, systemic lupus erythematosus nephritis, bacterial endocarditis, and membranoproliferative glomerulonephritis. A high antistreptolysin (ASO) titer suggests a recent streptococcal infection. Anti-DNase B levels are also 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. Antinuclear antibody (ANA) titers and the measurement of double-stranded DNA (dsDNA) levels are most helpful in children with suspected systemic lupus erythematosus nephritis.

A midstream or clean-catch specimen of urine should be obtained for culture sensitivity whenever a urinary tract infection is suspected. This is especially important in younger children, in whom classical symptoms of a urinary tract infection may be absent.

Renal and bladder ultrasonography

Macroscopic hematuria in the absence of significant proteinuria or RBC casts is an indication for a renal and bladder ultrasound study to exclude malignancy or cystic renal disease.[12]

Urinary tract anomalies, such as hydronephrosis, hydroureter, nephrocalcinosis, tumor, and urolithiasis, are readily revealed with ultrasonography. Compared with 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 be achieved using only CT scanning.

Other imaging studies

A spiral CT scan is particularly useful in the detection of urolithiasis, Wilms tumor, and polycystic kidney disease. 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. Cystoscopy can be considered if there is suspicion of urothelial papilloma on ultrasound studies.[12]

Intravenous urography rarely contributes additional information in the evaluation of hematuria and may unnecessarily expose the child to ionizing radiation.

A kidney biopsy is rarely 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.[13] 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

Cystoscopy is not generally required in children with nonglomerular hematuria. The only indication is a suspicious bladder mass revealed on ultrasonography.

Skin biopsy with immunostaining for the α5(IV) chain is particularly useful when suspicion of X-linked Alport syndrome is high.

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.

Table. Histologic Findings (Open Table in a new window)

A comprehensive physical examination and a detailed history are indispensable to the evaluation of hematuria.

A urinalysis should be obtained (as described above), and a careful microscopic review of the sample should be performed. Examples of microscopic findings are shown in the images below.

Microscopy of urinary sediment. Typical appearance in non-glomerular hematuria: RBCs are uniform in size and shape but show two populations of cells because a small number have lost their hemoglobin pigment.

Microscopy of urinary sediment. Typical appearance of RBCs in glomerular hematuria: RBCs are small and vary in size, shape, and hemoglobin content.

Microscopy of urinary sediment. A cast containing numerous erythrocytes, indicating glomerulonephritis.

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, whereas 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 above.

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 suggest membranoproliferative glomerulonephritis or systemic lupus erythematosus 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 the images below.

Approach to hematuria.

Nonglomerular hematuria.

Categorizing patients with hematuria into one of the following groups is helpful:

• Gross hematuria
• Microscopic hematuria with clinical symptoms
• Asymptomatic microscopic hematuria with proteinuria
• Asymptomatic microscopic (isolated) hematuria

Gross hematuria

Gross hematuria is alarming for the child's parents and sometimes for their pediatricians. Gross hematuria is an uncommon finding in an unselected population of children. The prevalence of gross hematuria was reported as 0.13%, based on a retrospective review of children seen in an emergency walk-in clinic.

Most children with gross hematuria (56%) have an easily recognizable and apparent cause. The most common diagnoses include urinary tract infection, perineal irritation, trauma, meatal stenosis with ulceration, coagulation abnormalities, and urinary tract stones.

Less than half (44%) of children with gross hematuria had a cause that was either not obvious or that required additional or more sophisticated examinations. Among the diagnoses in this group are recurrent gross hematuria, acute nephritis, ureteropelvic junction obstruction, cystitis cystica, epididymitis, tumor, hyperuricosuria, and hypercalciuria. These children require referral to a pediatric nephrologist for detailed investigation and management.

The time of occurrence of gross hematuria can also provide important clues regarding the etiology. When it occurs at the beginning of the urine stream, it is likely to be urethral in origin, whereas when it occurs mid-stream or late-stream, it likely originates from higher in the genitourinary tract. In physically active children without other symptoms, transient asymptomatic gross hematuria can be noted following vigorous exercise.[14]  Gross hematuria accompanied by upper respiratory tract symptoms could suggest IgA nephropathy (generally simultaneously or within a week)  or post-infectious glomerulonephritis (within 2 to 3 weeks).[1]

Microscopic hematuria with clinical symptoms

A child who presents with either symptoms of an illness or a physical abnormality and is discovered to have concurrent microscopic hematuria should be placed in this category. Some of the clinical conditions with associated renal involvement that may be recognized by the primary physician are acute glomerulonephritis, acute interstitial nephritis, urinary tract infections, familial hematuria (both benign recurrent and progressive hereditary nephritis), Henoch-Schönlein purpura, systemic lupus erythematosus, hypertension, hypercalciuria, and urolithiasis.

Unless the patient falls into a clear category of illness that is easily identified, an early consultation with the pediatric nephrologist should be obtained, because most other illnesses require additional expertise in either delineation or management. The child with microscopic hematuria associated with clinical symptoms may have a vast number of diseases or conditions, which makes this a difficult category for which to suggest specific evaluation.

The first step in this category is to direct the evaluation based on the symptoms or physical examination findings. The extent and thoroughness of the evaluation depends on the knowledge and experience of the physician.

Microscopic hematuria that is accompanied by fever or other infectious symptoms could be indicative of IgA nephropathy or urinary tract infection. A history of hematuria that accompanies painful crises in patients of African descent should raise suspicion for sickle cell nephropathy.

The child with a complicated diagnosis or unexplained cause for the hematuria should be referred to a pediatric nephrologist or, in some cases, to an appropriate subspecialist. If a diagnosis is straightforward, the appropriate therapy or follow-up is administered.

If the child has recurrence of the symptoms and associated hematuria or if the hematuria is persistent, referral to a pediatric nephrologist is recommended.

Asymptomatic microscopic hematuria with proteinuria

In the asymptomatic child, simultaneous microscopic hematuria and proteinuria (>50 mg/dL) in 3 consecutive urine samples is unusual and occurred in the Galveston study, with a prevalence of 64 per 100,000 school children (approximately 0.06%).[15] All of the children in this survey who were thought to have significant renal disease were included in this group. Despite the obvious concern attendant to this combined finding, almost 50% of the children who were discovered to have both hematuria and proteinuria had spontaneous resolution of both findings during the course of the 5-year follow-up.[16]

The significance of the renal involvement, in most cases, correlates directly with the quantity of protein being excreted. Thus, the combination of asymptomatic microscopic hematuria and proteinuria seems to suggest that such patients are more likely to have significant renal disease.

The first step in this category is to quantitate the urine protein at the initial or follow-up visit. Asymptomatic patients who are found to have both hematuria and proteinuria in several samples collected over a few weeks should be referred to a pediatric nephrologist for further evaluation and recommendations, because these findings point toward a glomerular origin.

Asymptomatic microscopic (isolated) hematuria

Asymptomatic microscopic hematuria is common in unselected populations of children. The discovery of hematuria alone in an asymptomatic child is merely an indication for repeat testing on one or more occasions.

The Galveston County epidemiology study found that, of children who had 3 consecutive urine samples that demonstrated hematuria, only 37% had hematuria 1 year later.[15] Thus, the cause for the asymptomatic hematuria had apparently resolved in 63% of the children over the course of a single year. Significant renal disease was almost nonexistent in patients in whom hematuria was the only abnormality found.

In cases involving the development of proteinuria or pyuria, the condition of isolated asymptomatic hematuria is no longer observed, and other studies should be performed. If the microscopic hematuria persists unchanged for more than 1-2 years, a few additional studies may be indicated.

One possible entity responsible for such an asymptomatic persistence of hematuria is idiopathic hypercalciuria or hyperuricosuria. Familial or hereditary hematuria, whether benign, nonprogressive (ie, "thin basement membrane disease"), or progressive (ie, Alport syndrome or one of its variants), is another condition in which, early in the course, hematuria may be found in the absence of proteinuria. IgA nephropathy may also present with microhematuria.

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 intervention may be necessary in certain anatomic abnormalities, such as ureteropelvic junction obstruction, tumor, or significant urolithiasis.

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).

Referral to a urologist is required when clinical evaluation and workup indicates a tumor, a structural urogenital abnormality, or an obstructing calculus.

Diet

Dietary modification is usually 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 recommended daily amount (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.

Patients with persistent microscopic hematuria should be monitored at 6-month 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.