February 15, 2005
Hematuria in Adolescents
case 1: Microscopic hematuria (5-10 red blood cells [RBC] per high power field [hpf]) was discovered during a physical examination for participation in team sports in an asymptomatic 14-year-old girl. No proteinuria or pyuria was found, and the physical examination was entirely normal. No family history of renal disease existed. Microscopic hematuria (5-10 RBC/hpf) persisted in a subsequent urinalysis. After a renal ultrasound examination was normal, the girl was referred for a consultation with a pediatrie nephrologist.
case 2: A 13-year-old male came to the emergency room with his first episode of gross hematuria. His urine was described as bright red in color. He had been afebrile and denied any pain. His past medical history was significant for an arteriovenous malformation of his right carotid artery. His physical examination was remarkable for an extensive nevus flamus on the right side of his trunk and hemihypertrophy of his right hand. He had normal blood pressure, blood urea nitrogen, creatinine, coagulation, complete blood count, and renal ultrasound with doppler examination. He had trace urine protein on dipstick and eumorphic RBC too numerous to count on his urine microscopy. On the grounds that urgent glomerular or urologie sources of his blood had been excluded, he was discharged with a nephrology clinic follow-up in 1 week. His urine cleared of gross blood after three voids. One week later, in nephrology clinic, the microscopic examination revealed no hematuria on urine dipstick or microscopy.
case 3: A 16-year-old Hispanic male, who had recently immigrated to the United States and had had no routine health care, came to a pediatrician for the first time. His school nurse referred him for an evaluation because of complaints of joint pain, which had been present for the past 2 months. His urine had been brown for 2 weeks. His blood pressure was 150/92 mm Hg, and he had mild pretibial edema, bilateral knee tenderness, and a malar rash. Urine dipstick had 3+ proteinuria and hematuria. Urine analysis revealed more than 100 dysmorphic RBC per hpf, as well as RBC and hyalin casts.
As these three cases indicate, hematuria in an adolescent can be due to a variety of causes with a wide range of severity. Adolescence is a time of transition from childhood to adulthood, and patients in this age range can develop medical problems that are more commonly anticipated earlier in childhood or, conversely, later during adulthood. Therefore, as with other medical issues in the adolescent years, the intervening clinician must consider an appropriate range of pediatrie and adult medical conditions when evaluating the adolescent with hematuria. In this article, the authors present an approach for the generalist clinician when encountering an adolescent with hematuria.
In the initial work-up of an individual with changes in urine color, a urine microscopic examination is required to determine whether the change is due to the presence of blood. Some pigments and crystals, when present at a significant concentration, will cause color changes in the urine that can be misinterpreted as hematuria. Such discoloration can be derived from rhabdomyolysis, intravascular hemolysis, and a number of foods, drugs, and metabolic disorders. For a partial list of substances that can cause red- brown urine discolorations, see Table 1 [1-3].
Causes of urinary discoloration potentially misinterpreted as gross hematuria in adolescents
Finding RBC during urine microscopic evaluation is the first step in the diagnosis of hematuria. The amount of blood required for the diagnosis of microscopic hematuria has varied. Some investigators have used a definition of greater than two RBC per hpf in 12 mL of a midstream urine specimen spun at 1500 RPM for 5 min . Others have used a criterion of greater than five RBC per hpf in a fresh, unspun midstream specimen . To further complicate the picture, others have used a definition of 10 RBC per hpf in a midstream urine collection . A study using more stringent criteria has greater positive predictive value with regard to presence of disease but loses some negative predictive power. Regardless of the specific criterion used by the clinician, important cofactors to consider when a patient has hematuria include urinary casts, the presence of proteinuria, a family history of renal or urologie disease, hypertension, and other clinical or laboratory findings suggestive of kidney or urinary tract disease. Whether the hematuria is visible (gross hematuria), is associated with symptoms, or is discovered incidentally in microscopy of the urine will dictate the urgency and scope of the evaluation.
Incidence and prevalence
Screening studies in children of all ages have found that microscopic hematuria varies in prevalence from 0.5% to 2.0%, depending on the population screened and (as already discussed) on the criterion used to make the diagnosis [5-7]. In adolescents, up to 6% may have hematuria on a single urinalysis; however, the prevalence falls substantially when urinalysis is repeated . Vehaskari et al  performed urinalyses in 8954 school-aged children, aged 8 to 15 years, and found that 1.1% of the children had hematuria in two or more specimens. In these Finnish children, the prevalence of hematuria was neither age- nor sex-dependent. Dodge  performed a large longitudinal screening study in children aged 6 through 12 years. In this study, hematuria was two to three times more prevalent in girls, particularly in adolescent girls. From 1974 to 1986, a national Japanese urinary screening program evaluated 380,000 elementary school children and 180,000 junior high students (12-14 years of age) . The prevalence of hematuria in junior high students was 5.13% in the first urine screening and fell to 0.94% on repeat urinalyses. Hematuria was more common in Japanese girls at all ages.
Gross hematuria in children is less common and accounts for only 1 of eveiy 1000 outpatient pediatrie visits . Among 153 children evaluated for gross hematuria in a general practice, the mean age was 7.4 years, the median age was 8 to 9 years, and the peak was 3 to 4 years. Gross hematuria was more likely because of urinary infection in girls at all ages.
In the screening study by Dodge , renal disease was not discovered among the adolescent children with hematuria. In the Finnish study, two children older than 10 years had renal disease (IgA nephropathy and hereditary nephritis). Diagnoses did not differ between the groups of adolescents and younger children in this study , In the Japanese screening study, the prevalence of nephritis was 0.004% in junior-high children . Incidental hematuria in adults has also been shown to be benign. Fewer than 2% of adults with hematuria have a serious and treatable urinary tract disease .
The lack of important diagnoses uncovered in adolescents examined in these screening studies, together with the costs of evaluating microscopic hematuria, indicates that routine screening has little value [1O]. Currently, screening for hematuria among adolescents is not recommended.
Differential diagnoses of hematuria in adolescents
Entities that cause hematuria in adolescents may be divided into three groups: late emergence of childhood conditions, adolescent conditions, and early presentation of adult diseases.
Late emergence of childhood conditions
Conditions that are usually encountered in younger children but may emerge in adolescents include structural malformations of the genitourinary tract. In particular, abdominal trauma may lead to hematuria in a previously unsuspected obstructed urinary tract. Genetic conditions, such as cystinuria, occasionally escape detection until adolescence. Hypercalciuria without urolithiasis is another cause of hematuria in younger children but has been initially identified in some adolescents as well [U]. Acute glomerular and vascular diseases, such as poststreptococcal glomerulonephritis and hemolytic uremie syndrome, may present during adolescence. Some chronic nephropathies, such as Alport's disease and thin basement membrane disease, may manifest in adolescence as well as earlier during childhood.
Diagnoses typical of adolescence
Urinary tract infections, both bacterial and viral, may be associated with hematuria at any age but emerge as an important diagnosis during adolescence. In sexually active teenagers, cystitis and urethritis should be considered when evaluating hematuria, and specific symptoms should be questioned. Urinary infections may present with either gross or microscopic hematuria and are the most common cause of gross hematuria in girls in a pediatrie office setting . However, the diagnosis of urinary infection requires a positive culture and should not be based only on the presence of urinary RBC.
Adolescents may present with various glomerular disorders. In a study of 56 adolescents aged 13 to 19 years who underwent renal biopsy for gross hematuria without nephrotic syndrome, 29 patients had IgA nephropathy and 20 had non-IgA mesangial lesions . Lupus nephritis should be considered in adolescents, especially when systematic symptoms are present. Interstitial nephritis may also occur in adolescents. Analgesic nephropathy and papillary necrosis should be considered in adolescents, who may be experimenting with a number of drugs, herbs, or potential nephrotoxins.
Hypercal\ciuria may produce hematuria without urolithiasis; moreover, urinary calculi are seen more commonly in adolescents than in younger children [U]. Exercise, especially long-distance running or other jarring physical activity, may produce hematuria in adolescents. Vascular malformations and coagulopathies are uncommon causes. Factitious hematuria should be considered if the history does not fit the clinical situation.
Conditions more commonly seen in adults
Occasionally, conditions more commonly seen in adults become clinically active in adolescents. Examples of such conditions are gout, autosomal dominant polycystic kidney disease, medullary sponge kidney, and renal cell carcinoma . Hematuria without symptoms is extremely uncommon as a presenting sign of malignancy in children. In large population screening studies, occult malignancies have not been reported in asymptomatic children with hematuria.
Evaluation of the adolescent with hematuria
When a patient is found to have hematuria, either as a presenting symptom or by screening evaluation, obtaining a careful history and physical examination is a crucial first step in the diagnostic process. The clinician should consider the list of causative factors in the previous discussion. A history of family members with hematuria or a history of marathon running, for instance, might direct the clinician to the diagnosis of familial hematuria or exercise-induced hematuria. Such clues from the history and specific findings during the physical examination occasionally make possible a more targeted evaluation. In most instances of minimal microscopic hematuria, the patient is asymptomatic and has a normal physical examination.
When considering the presenting complaint of gross urinary blood, it is helpful to ascertain both the timing of the urinary changes in terms of days or hours and the associated symptoms. Questions should specifically deal with recent trauma, passage of urinary stones or gravel, and recent respiratory or systemic infections. Fevers, dysuria, urinary frequency, or back pain raise the possibility of a urinary infection. Patients should be asked about their energy level, weight changes, night sweats, face and leg swelling, skin rashes, joint symptoms, headaches, cough or chest pain, and diarrhea. It is also important to inquire whether the patient has had previous urinalyses to determine the chronicity of the hematuria.
Medication history needs to include not only medications prescribed by physicians but also homeopathic and over-the-counter medications. Sometimes these medications are considered by families to be insignificant dietary supplements, when they may in fact be the source of renal pathology. For example, excessive vitamin D or calcium supplementation could trigger hypercalciuria, and high doses of ascorbic acid can produce crystalluria. Some herbs taken for appetite suppression have triggered interstitial nephritis , Past medical history should include questions about hearing, vision, and growth concerns.
Family history should search for documented hematuria, hypertension, recurrent urinary tract infections, kidney abnormalities (including cystic disease), kidney stones, kidney failure, glomerulonephritis, deafness, and autoimmune diseases. Social history should take account of any recent sexual activity and any known exposure to sexually transmitted diseases.
The physical examination should focus on blood pressure, growth measures, rashes or cutaneous manifestations of tuberous sclerosis or neurofibromatosis, retinal lesions, hearing, cardiac findings, the abdominal organs, pelvic organs, and genitalia, and edema (ie, facial, pretibial). For example, the finding of hemihypertrophy in a previously unsuspected case of Beckwith Wiedemann syndrome might lead to the diagnosis of medullary sponge kidney .
The urinalysis with microscopic examination often directs the evaluation. When hematuria is present, the key additional components of the dipstick urinalysis are the presence or absence of protein, leukocytes, and glucose. Proteinuria in an adolescent with hematuria suggest glomerular or interstitial disease. Leukocytes suggest the possibility of a urinary infection. Glycosuria might suggest diabetes mellitus, renal tubular disorders, or focal segmental glomerular sclerosis.
Microscopic examination of the urine sediment is important in evaluating hematuria. When urinary RBC are present in the urine, the clinician can evaluate the shape of the cells to delineate the site of bleeding within the urinary tract. In a fresh sample, RBC that are more than 90% to 95% eumorphic (ie, of normal size and shape) are most commonly from the lower urinary tract; cells that are dysmorphic (ie, acanthocytes of various sizes) are more likely to be of glomerular origin . When white blood cells (WBC) are found, the presence of infection and interstitial or glomerular inflammatory disorders should be considered. Interstitial nephritis is even more likely if Wright stain of the urine shows the presence of eosinophils. Infections and poststreptococcal nephritis often have neutrophils in the urinalysis. The presence or absence of cellular casts is very important. RBC casts suggest glomerulonephritis, WBC casts are seen with pyelonephritis and renal inflammatory disorders, and casts of tubular cells are often seen in individuals with acute tubular necrosis. Fatty and broad casts are most often found in individuals with a more chronic disease state.
When crystals are visible in the urine and the patient has other findings suggestive of nephrolithiasis, knowledge of the pH of the urine and shape of the crystals can help elucidate the chemical nature of the offending stone. Calcium oxalate crystals may point to hypercalciuria.
Laboratory and radiologie evaluation
When microscopic hematuria without proteinuria is discovered in an otherwise normal adolescent, additional early-morning urines should be tested over a period of 6 to 12 weeks to verify that RBC are consistently present (Fig. 1). At present, there is little evidence that evaluation of incidental hematuria is of value . Nonetheless, current practice is to obtain a urine culture, urine calcium-tocreatinine ratio, and renal ultrasound examination. In a group of 115 teenagers with microscopic hematuria, 16% had a family history of hematuria . Hence screening family members for hematuria may be worthwhile.
If urinary calcium oxalate crystals are present, then urine calcium excretion should be assessed with a urine calcium-to- creatinine ratio (normal
* 24-hour urine calcium excretion
* Serum calcium, phosphorus, sodium, potassium, chloride, bicarbonate, magnesium, creatinine
* Renal ultrasound examination
If the urinary dipstick is also positive for protein, protein excretion should be assessed by a urine protein-to-creatinine ratio (normal
* Quantity of urine protein excretion
* Serum creatinine (estimate glomerular filtration rate)
* Blood urea nitrogen
* Serum albumin
* Antistreptococcal antibodies
* Serum complement concentrations (if hypocomplementimia, obtain anti-nuclear antibody, hepatitis profile)
* Antinuclear antibody if symptoms suggest lupus
When gross hematuria occurs, more emphasis is given to the evaluation, although no diagnosis results in 9% to 33% of such patients , see Fig. 1 for a framework for evaluating gross hematuria. When a urinary stone is identified, a complete assessment of stone-risk urinary constituents is needed .
Fig. 1. Evaluation of hematuria. (History or physical examination may supersede.) Ca/Cr, calcium-to-creatinine ratio.
Referral to a pediatric nephrologist or urologist is seldom required for microscopic hematuria. Gross hematuria often leads to a consultation, depending on its cause. Renal biopsy is reserved for those with hematuria and proteinuria not associated with poststreptococcal glomerulonephritis, hypocomplementemia, persistent gross hematuria, and hematuria with unexplained azotemia.
The three cases presented in the introduction to this paper demonstrate that blood in the urine can derive from a wide range of medical problems of various degrees of severity. Hematuria may result from a focal urogenital process or from a more complex, systemic disease state. When approaching these adolescent patients, we can now apply the considerations discussed earlier with regard to history, physical examination, and laboratory findings.
Case 1 : Microscopic hematuria without proteinuria in this asymptomatic girl persisted. The urinalysis demonstrated 5 to 10 eumorphic RBC per hpf. No family history of urinary stones existed and no crystals were observed in the urine. A renal ultrasound obtained by the primary care physician was normal. An extensive history revealed no sports activities, bicycle riding, or other trauma. As the patient was leaving the consultation, she mentioned that she was going skiing with her family the next day. When this information was explored further, the authors learned that she was a competitive snowboarder and routinely did jumps. They re-examined her during the summer and found no hematuria. She had "exercise- induced" hematuria. No laboratory studies were obtained.
Case 2: An asymptomatic, normotensive teenager with short-lived gross hematuria had many findings on physical examination that were suggestive of a vascular source of blood. His mucous membrane varicosities, extensive cutaneous nevus flamus, hemihypertrophy of the third phalanx, and history of arteriovenous malformation in his neck were all unusual findings; he had received no unifying diagnosis before presenting to the emergency room with gross hematuria. The blood in his urine was gross and painless, and wi\thin days his urine was clear of even microscopic blood. The cells were eumorphic, and his renal function was completely normal. The constellation of his history and physical examination findings is explained by a syndrome resulting in multiple, systemic vascular anomalies, the Klippel-Trenaunay Weber syndrome . The source of blood in the urine of these individuals can be from vascular malformations anywhere along the urogenital tract. Recurrent or recalcitrant bleeds can require surgical intervention. Fortunately, the authors' patient has never had a recurrence.
Case 3: This 16-year-old male had systemic history and physical examination findings consistent with an active inflammatory process. His elevated blood pressure, leg edema, brown urine, and urinalysis examination revealing dysmorphic RBC and RBC casts suggested a glomerular source of hematuria. His joint involvement and skin rash were findings consistent with systemic lupus erythematosus. His blood work revealed a positive antinuclear antibody and antidouble- stranded DNA, and his renal biopsy revealed diffuse, proliferative glomerulonephritis. He is currently being treated with monthly cytoxan and prednisone therapy, and his disease is in remission.
Hematuria is not a rare finding during adolescence. The high prevalence of microscopic hematuria is not surprising when one considers the vast number of ways in which RBC can end up in the urine. The adolescent presenting with gross hematuria, proteinuria, or microscopic hematuria in combination with other symptoms of genitourinary disease is more likely to require a therapeutic intervention than is the individual found incidentally to have microscopic hematuria. Screening for hematuria is not supported by current evidence. When it is discovered as the result of a screening examination, persistent microscopic hematuria in an otherwise asymptomatic individual may not require further investigation; however, the renal ultrasound examination has little risk and is helpful in diagnosing many of the conditions amenable to intervention. Serum studies offer little useful information in the evaluation of microscopic hematuria. Addressing isolated hematuria in a systematic, evidence-based fashion can help avoid untoward patient and parental worry and excessive health care costs, without missing treatable or progressive disease entities.
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Carrie Gordon, MDa, F. Bruder Stapleton, MDb'*
a Division of Pediatrie Nephrology, University of Vermont College of Medicine, Barbara Bush Children s Hospital, Maine Medical Center, 887 Congress Street, Suite 320, Portland, ME 04102, USA
b Children's Hospital and Regional Medical Center, Department of Pediatrics T-0211, University of Washington, 4800 Sand Point Way NE, Seattle, WA 98105, USA
* Corresponding author.
E-mail address: [email protected] (F.B. Stapleton).
Copyright Hanley & Belfus, Inc. Feb 2005