Elaine S. Kamil, MD
A 6-year-old boy is brought to the office for a school entry examination. He was the full-term product of an uncomplicated pregnancy, labor, and delivery. Although he has had 4 or 5 episodes of otitis media, he has generally been in good health. He has never been hospitalized or experienced any significant trauma. He has no known allergies, has been fully immunized, and is developmentally normal. However, his mother states that he has reported occasional mild abdominal pain.
The physical examination is completely normal. Height and weight are at the 75th percentile, and blood pressure is 100/64 mm Hg. Screening tests for hearing and vision are normal. Hematocrit is 42. The urinalysis comes back with a specific gravity of 1.025, pH 6, 2+ blood, and trace protein. Microscopic examination shows 18 to 20 red blood cells per high-power field; 0 to 1 white blood cells per high-power field; and a rare, fine, granular cast.
1. What disease entities cause hematuria?
2. How should hematuria be evaluated?
3. How does the approach to hematuria differ in children who report dark or red urine?
4. What is the appropriate follow-up of children with asymptomatic microscopic hematuria?
Hematuria is a common problem in pediatric patients, and primary care physicians should have a clear understanding of its pathophysiology, etiology, evaluation, and therapy. Hematuria can be caused by a serious medical problem, or it may be only an incidental finding with no potential for impairment of patient health. Generally, hematuria is categorized as gross or microscopic. The etiology of and approach to hematuria vary based on the severity and symptomatology. Gross hematuria is defined as red or brown urine caused by the presence of red blood cells (RBCs). Microscopic hematuria is defined as 3 or more consecutive urine samples with a positive dipstick and 6 or more RBCs per high-power field in a fresh, spun urine sample.
Table 109.1. Etiology of Gross Hematuria in an Unselected Pediatric Population
Meatal stenosis with ulcer
Recurrent gross hematuria
Ureteropelvic junction obstruction
Abbreviation: UTI, urinary tract infection.
Adapted with permission from Ingelfinger JR, Davis AE, Grupe WE. Frequency and etiology of gross hematuria in a general pediatric setting. Pediatrics. 1977;59(4):557–561.
The prevalence of gross hematuria is approximately 1.3 in 1,000 patient visits (Table 109.1). In 1 series, the causes in approximately one-half of the patients were readily apparent from the intake history or physical examination. The incidence of gross hematuria may increase in the community during an epidemic of a disease, such as acute glomerulonephritis, a condition often associated with gross hematuria. In another series, approximately 30% of children with gross hematuria had glomerular diseases, most commonly immunoglobulin (Ig) A nephropathy. The incidence of kidney stones, another cause of hematuria, is increasing in the pediatric population.
Microscopic hematuria is a more common problem among pediatric patients. Prevalence rates for persistent microscopic hematuria range from 0.5% to 2.0%, but 4% to 5% of school-age children may have microscopic hematuria on a single voided specimen. The incidence is artificially increased in the summer because at that time children tend to visit pediatricians for camp and preparticipation sports physical examinations that typically include a screening urinalysis.
The child with gross hematuria presents with the sudden appearance of red or brown urine, which may be associated with flank or urethral pain or with a history of trauma. It may occur during or within 1 to 2 weeks of a respiratory infection.
The child with microscopic hematuria may have urinary symptoms (eg, dysuria). In the child who appears well, microscopic hematuria is usually detected on screening dipstick examination or on urinalysis obtained for other indications. In 2007 the American Academy of Pediatrics ceased recommending that routine screening urinalysis be done in asymptomatic children and adolescents. Urinalysis often is still requested as part of camp and preparticipation sport evaluations, however. In Japan, because of a high incidence of glomerulonephritis (primarily IgA nephropathy), annual screening urinalysis is performed in schools and seems to have had an effect on early diagnosis and treatment.
Gross hematuria occurs because of the presence of large numbers of RBCs in the urine. Blood may enter the urine because of rupture of blood vessels following trauma or inflammation in the glomeruli or interstitial regions of the kidney. It also may occur as a result of severe inflammation of the bladder wall.
Causes of gross hematuria are listed in Box 109.1. The presence of casts in the urine indicates that the red cells are coming from the glomeruli and suggests the diagnosis of glomerulonephritis. The most common causes of glomerulonephritis in children include acute postinfectious glomerulonephritis (most commomly poststreptococcal), anaphylactoid purpura (ie, Henoch-Schönlein purpura), IgA nephropathy, membranoproliferative glomerulonephritis (MPGN), dense deposit disease, and systemic lupus erythematosus (SLE).
Common causes of gross hematuria in the absence of RBC casts include urinary tract infection from bacteria or certain viruses, renal trauma, bleeding diathesis (eg, hemophilia, idiopathic thrombocytopenic purpura), renal tumors, obstruction of the urinary tract, renal stones, hypercalciuria, and hemolytic uremic syndrome (HUS). Hemangioma in the urinary tract is an extremely rare cause of gross hematuria. In endemic areas, gross hematuria may be caused by schistosomiasis. Another rare cause of gross hematuria is nutcracker phenomenon caused by left-sided renal vein congestion from compression of the renal vein by the superior mesenteric artery. The symptoms of nutcracker phenomenon are distinctive: intermittent gross hematuria associated with left-sided flank pain that is relieved by lying down. Another cause is urethrorrhagia, in which children, typically prepubertal boys, pass bloody urine, usually at the end of their voiding and frequently accompanied by spots of blood in the underwear.
Box 109.1. Common Causes of Gross Hematuria in Pediatric Patients
•Acute postinfectious GN
•Dense deposit disease
•Anaphylactoid purpura GN
•Thin basement membrane disease
•Rapidly progressive GN
•Vasculitis, ANCA positive
•Anti–glomerular basement membrane disease
•Hemolytic uremic syndrome
•Sickle cell disease or trait or hemoglobin C
•Thrombosis (renal arterial or venous)
•Polycystic kidney disease
•Bacterial urinary tract infection
•Acute interstitial nephritis
•Tubulointerstitial nephritis with uveitis
•Munchausen by proxy
Abbreviations: ANCA, antineutrophil cytoplasmic autoantibody; GN, glomerulonephritis; IgA, immunoglobulin A.
Microscopic hematuria occurs when small numbers of RBCs enter the urine via tiny ruptures in the glomerular capillary walls or in the capillaries of the tubulointerstitium or bladder lining. One study showed that otherwise healthy children with microscopic hematuria had increased erythrocyte deformability, making it easier for RBCs to slip through the glomerular capillaries. For purposes of discussion, the following causes of microscopic hematuria are considered: infectious, structural, traumatic, glomerular, and interstitial. Separate consideration of the causes of microscopic and gross hematuria often is helpful, although significant overlap exists. The presence of gross hematuria typically warrants a more rapid, and usually more extensive, evaluation.
Urinary tract infection is among the most common infectious causes of hematuria. Bacterial infections of the bladder or kidney occur much more frequently than viral cystitis. Adenovirus is the most common viral cause of hemorrhagic cystitis and usually is associated with dysuria. Other viral causes include cytomegalovirus, parvovirus 19, and BK polyomavirus nephropathy. Vaginitis in girls and prostatitis in teenage boys also may result in hematuria.
Any type of congenital obstructive uropathy may result in massive dilatation of the urinary tract, which increases the susceptibility for bleeding of the urinary tract, even with trivial trauma. Chronic urinary tract obstruction in children (eg, posterior urethral valves, congenital ureteropelvic junction obstruction) is often asymptomatic. Historically, these conditions typically were diagnosed when children presented with urinary tract infections or gross hematuria after relatively trivial trauma. Currently, congenital urinary tract obstruction typically is diagnosed after a prenatal ultrasonography reveals hydronephrosis in the fetus. Nevertheless, urinary tract obstruction may be detected during an evaluation for asymptomatic microscopic hematuria.
Any tumor of the genitourinary tract may be associated with gross and microscopic hematuria. Pelvic tumors rarely cause urinary obstruction in children, although such tumors frequently cause obstruction in adults. The child with Wilms tumor, the most common childhood renal tumor, usually presents with an abdominal mass but may experience hematuria.
Congenital renal malformations are quite common. Any of these may be associated with hematuria and include polycystic kidney disease, renal dysplasia, medullary sponge kidney, and simple cysts. Patients with polycystic kidney disease may have severe, painful hematuria.
Vascular problems may result in hematuria. Hemangiomas of the kidney, bladder, or ureter are quite rare but may bleed. Arteriovenous malformations also occur infrequently. Hematuria may be a sign of a renal artery or renal vein thrombosis, particularly in sick neonates.
Young children are more susceptible to renal injury, which may result in hematuria, than older children or adults because their kidneys are relatively less protected by the rib cage. Additionally, children may insert foreign objects into the vagina, urethra, and bladder that cause pain and hematuria. Microscopic hematuria has also been described after extremely vigorous exercise, such as mar-athon running. Child abuse or Munchausen syndrome by proxy should be considered if any suspicions are raised on the basis of the history or physical examination.
Hypercalciuria is another cause of microscopic hematuria. The child with hypercalciuria often has a family history of urinary calculi. Calcium oxalate crystals may be present on microscopic examination of the urine. A urinary calcium-creatinine ratio is best obtained on a first morning, fasting urine sample with reminders to the family that the child should empty the bladder before going to bed. Urinary calcium excretion varies with age. Normal values are listed in Table 109.2.
The 2 types of hypercalciuria are absorptive and renal leak. The child with absorptive hypercalciuria overabsorbs calcium from the gastrointestinal tract, likely because of an exquisite sensitivity to vitamin D, and can be treated with a reduced calcium diet to the recommended daily allowance for age. The child with renal leak hypercalciuria has an inherently higher rate of urinary calcium excretion and may require thiazide diuretics to reduce urinary calcium excretion. Interstitial nephritis, usually resulting from drug exposure, may also cause hematuria. Generally, the patient with interstitial nephritis may exhibit other signs of tubular disease, such as glycosuria, polyuria, or proteinuria.
Glomerular disease may cause gross or microscopic hematuria. Etiologies include acute or chronic glomerulonephritis, such as acute postinfectious glomerulonephritis, MPGN, dense deposit disease, antineutrophil cytoplasmic antibody–associated vasculitis, IgA nephropathy, SLE, thin basement membrane disease or nephropathy, and Alport syndrome. The RBCs originating from glomeruli are dysmorphic, and careful examination of the urine from these patients often reveals RBC casts.
Sickle cell disease, sickle cell trait, and hemoglobin C trait have been associated with gross or microscopic hematuria.
When a child reports red urine (ie, gross hematuria), the physician must first determine whether it is the result of hematuria or pigmenturia by using a urine dipstick. If the dipstick result is negative for blood, the dark urine is caused by dyes, drugs, or pigments (Table 109.3). If the dipstick is positive for blood, the red color is caused by intact RBCs, hemolyzed RBCs, hemoglobin, or myoglobin; the clarification is based on microscopic examination of fresh, spun urine.
Table 109.2. Normal Values for Urinary Calcium-Creatinine Ratiosa
|Age||Urine Calcium-Creatinine Ratio||24-Hour Urine Calcium|
19 months–6 years
a Samples for calcium-creatinine ratio should be obtained on a fasting, first-voided morning specimen. The calcium and creatinine concentrations must be in the same units (eg, mg/dL) before the ratio is calculated.
b For healthy preterm newborns taking no medications. Calcium excretion varies with diet and phosphorus intake, and it is higher if patients are treated with furosemide, xanthines, or glucocorticoids.
a Some common exogenous pigments include phenytoin, beets, rifampin, nitrofurantoin, sulfas, amitriptyline, methyldopa, phenothiazine, and chloroquine.
The child whose dipstick result is positive for blood but shows no RBCs may have hemoglobinuria or myoglobinuria, or the urine may have been improperly handled en route to the laboratory. Hemoglobinuria may be seen with acute autoimmune hemolytic anemia, drug-induced hemolysis, paroxysmal nocturnal hemoglobinuria, a mismatched blood transfusion, cardiopulmonary bypass, freshwater drowning, and, in some cases, HUS. Myoglobinuria is noted in individuals with rhabdomyolysis. Acute rhabdomyolysis can occur after a crush injury or a very prolonged seizure and in certain susceptible individuals with an inborn error of muscle metabolism. Myoglobinuria also may be occur with the myositis associated with influenza infections. Free hemoglobin and myoglobin are toxic to the renal epithelial cells, mandating generous fluid intake and close monitoring. Serum appears clear in myoglobinuria and pink in hemoglobinuria.
The history is crucial to an accurate, efficient, and cost-effective evaluation of patients with hematuria (Box 109.2). The family should be questioned carefully about trauma to the trunk, abdomen, or perineum; recent skin infection or pharyngitis; dysuria; and abdominal or flank pain. The presence of gross hematuria at the onset or the end of urination is associated with bleeding from the urethra or bladder trigone. Parents or guardians should be asked whether the child appears “puffy.” A family history of hematuria, kidney disease, hearing loss, SLE, bleeding diathesis, hemolytic anemia, or inborn error of muscle metabolism may be important in the diagnosis.
Box 109.2. What to Ask
•Has the child experienced any recent trauma?
•Has the child had fever or dysuria?
•Does the child have any flank or abdominal pain?
•Does the child have any rashes, joint pains, or edema?
•Does the child have a family history of hematuria, kidney disease, kidney stones, or gross hematuria?
•Is there a family history of bleeding disorders or inborn errors of muscle metabolism?