Assessment of Hematuria

Vitaly Margulis,
KEYWORDS  Microscopic hematuria  Gross hematuria  Differential diagnosis  Evaluation
MD*,

Arthur I. Sagalowsky,

MD

Hematuria is a common clinical finding in the adult population, with a prevalence ranging from 2.5% to 20.0%.1,2 Although gross hematuria is defined simply as visible urine discoloration because of the presence of blood, there is controversy regarding the exact definition of microscopic hematuria. The American Urological Association (AUA) guidelines define clinically significant microscopic hematuria as more than 3 red blood cells (RBCs) per high-power field on 2 of 3 properly collected urine specimens over a period of 2 to 3 weeks.3 However, patients at high risk for significant urologic disease (see later discussion) should be evaluated for hematuria if a single urinalysis demonstrates 2 or more RBCs per high-power field.4 Appropriate and timely evaluation is imperative, because any degree of hematuria can be a sign of a serious genitourinary disease.4,5 The focus of this article is on the logical and cost-effective evaluation of hematuria in adults, with specific attention directed to the indications and practice patterns for performing laboratory tests, imaging studies, and cystoscopy.

CAUSE

The most common causes of hematuria in adult populations include urinary tract infections, urolithiasis, benign prostatic enlargement, and urologic malignancy.1,2,4 However, the complete differential is extensive (Box 1). The incidence of specific conditions associated with hematuria varies with patient age, type of hematuria (gross or microscopic, symptomatic or asymptomatic), and existence of risk factors for urologic malignancy. Overall, approximately 5% of patients with microscopic hematuria and up to 40% of patients with gross hematuria are found to harbor a neoplasm of the genitourinary tract.3,5,6 Conversely, in up to 40% of patients with asymptomatic microhematuria, no identifiable source is found.1 As a result, a clinician should consider otherwise unexplained hematuria of any degree to be of a possible malignant origin, until proven otherwise.
The authors have nothing to disclose. Department of Urology, The University of Texas Southwestern Medical Center, 5339 Harry Hines Boulevard, Dallas, TX 75390-9110, USA * Corresponding author. E-mail address: Vitaly.margulis@utsouthwestern.edu Med Clin N Am 95 (2011) 153159 doi:10.1016/j.mcna.2010.08.028 medical.theclinics.com 0025-7125/11/$ see front matter 2011 Elsevier Inc. All rights reserved.

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Box 1 Causes of hematuria Urinary tract infection Urinary calculi Urinary tract malignancy Urothelial cancer Renal cancer Prostate cancer Benign prostatic hyperplasia Radiation cystitis and/or nephritis Endometriosis Anatomic abnormalities Arteriovenous malformation Urothelial stricture disease Ureteropelvic junction obstruction Vesicoureteral reflux Nutcracker syndrome Medical or renal disease Glomerulonephritis Interstitial nephritis Papillary necrosis Alport syndrome Renal artery stenosis Metabolic disorders Hypercalciuria Hyperuricosuria Coagulation abnormalities Miscellaneous Trauma Exercise-induced hematuria Benign familial hematuria Loin painhematuria syndrome

EVALUATION Diagnosis

The urinary dipstick test is the most common test used to evaluate urine and provides a semiquantitative analysis of the number of RBCs. Dipsticks detect 1 to 2 RBCs per high-power field and are therefore at least as sensitive as microscopic examination of the urine sediment.7 False-positive findings can be seen with hemoglobinuria, myoglobinuria, and urine contaminants; consequently, a positive test result (whether trace or 31) should immediately be followed by

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a microscopic examination of the urinary sediment to confirm or exclude the presence of RBCs.8 Correspondingly, gross discoloration of urine should not be presumed to be due to hematuria because a range of dietary, metabolic, and pharmacologic factors such as beets, blackberries, melanin, bile, porphyrin, iron, and various medications can also be responsible.
History and Physical Examination

Detailed and systematic patient history and physical examination should aim to elicit potential glomerular and extraglomerular causes of hematuria and to stratify patients according to their risk for urologic malignancy. Risk factors for urothelial cancer in patients with microscopic hematuria Smoking history Occupational exposure to chemicals or dyes (benzenes or aromatic amines) History of gross hematuria Age greater than 40 years History of urologic disorder or disease History of irritative voiding symptoms History of urinary tract infection Analgesic abuse History of pelvic irradiation. A thorough health history includes medical and surgical history, family history, social history, occupational or radiation exposure, and medications taken. For example, increased frequency and dysuria may suggest urinary tract infection, whereas colicky pain suggests urolithiasis. Presence of prostatism-related lower urinary tract symptoms, such as hesitancy, intermittency, and decrease in the force of the urinary stream, are usually due to benign prostatic enlargement. Recent upper respiratory tract or skin infection may be associated with glomerulonephritis. Recent menstruation, vigorous exercise, or sexual activities may produce transient hematuria in otherwise healthy patients. A family history of polycystic kidney disease and other renal diseases, sickle cell anemia, and a history of travel to areas with endemic schistosomiasis, malaria, or tuberculosis may be additional important clues to the cause of hematuria. The physical examination should focus on the detection of hypertension that is present along with nephritic syndrome and renal vascular disease, edema associated with nephrotic syndrome, palpable abdominal or flank mass suggesting a renal neoplasm, and costovertebral or suprapubic tenderness, common with urinary tract infection. A rectal examination in men may reveal prostatic nodularity or enlargement as a potential cause.
Laboratory Studies

Focused laboratory evaluation should be directed at the differentiation of glomerular and nonglomerular sources of hematuria and identification of potential associated systemic infections and inflammatory and immunologic conditions.3,9 Initial tests should include urinalysis with examination of the urinary sediment, complete blood cell count, estimation of serum creatinine and electrolyte levels, and urine culture. Patients with urinary tract infection should be treated appropriately, and urinalysis should be repeated 2 to 6 weeks after treatment. Similarly, patients with documented urinary tract calculi and asymptomatic microscopic hematuria should have a repeat

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urinalysis after stone clearance. Additional laboratory investigation should be guided by specific findings of the history, physical examination, and urinalysis. Formal urinalysis can aid in the identification of glomerular disease as the source of bleeding; this analysis being important for prognosis and optimization of subsequent evaluation. The presence of dysmorphic RBCs, RBC casts, or proteinuria (protein excretion exceeding 500 mg/d with no concomitant gross hematuria) supports a diagnosis of hematuria of glomerular origin, warranting nephrologic consultation.10 Urologic consultation and evaluation of the upper and lower urinary tracts is necessary in all patients with gross hematuria, and should be considered in high-risk individuals with microhematuria not associated with glomerular disease (Fig. 1).3,9,11

Fig. 1. Workup of hematuria in adults based on AUA best practice policy recommendations. (Data from Grossfeld GD, Wolf JS Jr, Litwan MS, et al. Asymptomatic microscopic hematuria in adults: summary of the AUA best practice policy recommendations. Am Fam Physician 2001;63(6):1148; and Adapted from Grossfeld GD, Wolf JS, Litwin MS, et al. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy recommendations. Part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology 2001;57(4):607; with permission.)

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Radiological Imaging of the Upper Urinary Tract

Several modalities are available to evaluate the upper genitourinary tract in patients with hematuria. These modalities include conventional radiography, intravenous pyelography, retrograde pyelography, ultrasonography, magnetic resonance imaging, magnetic resonance urography, conventional computed tomography (CT) scanning, and multidetector CT urography (CTU).1215 Table 1 summarizes limitations associated with these radiological imaging modalities. Because there are no data comparing the effect of various radiological modalities on the treatment of patients with hematuria, no formal guidelines for their use in the clinical setting have been established. However, most clinicians consider CTU to be the preferred initial imaging modality in most patients with unexplained hematuria.1417 CTU is a 3-phase CT scan with a noncontrast phase evaluating for urolithiasis, a contrast-enhanced phase for renal parenchymal abnormalities, and delayed images of the renal collecting system and ureters for pathologic conditions affecting the urothelial lining.15 AUA guidelines suggest that patients with microscopic hematuria who are found to be at low risk for urologic malignancy and urolithiasis from noncontrast CT scan do not need further imaging and exposure to intravenous contrast.3,9 Patients in whom contraindications to the administration of intravenous contrast exist can be effectively imaged with the selective use of noncontrast CT, ultrasonography, magnetic resonance imaging, and retrograde pyelography, depending on clinical history and suspected causes within the differential diagnosis.14 Urologic consultation may be of value.
Cystoscopy and Cytology

Even though the urinary bladder and its lumen can be visualized on radiological imaging, the lower urinary tract can only be adequately evaluated by cystoscopy. Consequently, direct visualization of the urothelium to determine the presence of lower urinary tract infection is mandatory in all patients at high risk for urologic disease. Modern cystoscopic equipment allows for well-tolerated, safe, and accurate assessment of the bladder and urethra in the outpatient setting.18 Patients who are found to have a bladder tumor by cystoscopy should still undergo an initial imaging study of the upper urinary tract because of the multifocal nature of urothelial carcinoma.3 Conversely, the identification of upper urinary tract infection does not preclude the need for cystoscopy. Cytologic evaluation of the urine demonstrates excellent sensitivity and specificity for high-grade urothelial carcinoma, but has limited (45%70%) sensitivity and specificity for low-grade disease, and requires an experienced cytopathologist for

Table 1 Imaging modalities for evaluation of the upper urinary tract and their limitations. Imaging Modality Intravenous Urography Retrograde Pyelography Ultrasonography Magnetic Resonance Imaging CTU Limitations Poor sensitivity for and ability to characterize renal parenchymal masses, intravenous contrast exposure Poor sensitivity for and ability to characterize renal parenchymal masses, invasive Limited ability to detect urolithiasis, small (<3 cm) renal mass, and urothelial abnormality Expensive, time consuming, poor sensitivity for urolithiasis Largest cumulative radiation exposure, expensive

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interpretation of the results.9 According to the AUA best practice guidelines, voided urinary cytology can be substituted for cystoscopy in patients without high-risk features for urologic disease (see Fig. 1).11 Cystoscopy can then be performed if malignant or suspicious cells are identified. However, cytology may be used as an adjunct to cystoscopy in high-risk patients. Because of the limitations of urinary cytology, several urine-based molecular tests for the detection of urothelial cancer have been developed (BTA stat, Polymedco Inc, Cortlandt, Manor, NY, USA; NMP-22, Matritech Inc, Newton, MA, USA; UroVysion, Vysis Inc, Downers Grove, IL, USA).19 However, the role of these tests in the detection and follow-up of patients at risk for urothelial cancer is not defined at present. These costly urine markers are therefore not currently recommended in the initial evaluation of patients with hematuria.9
Follow-up

A small proportion of patients (1%) with a negative result in the initial hematuria evaluation are subsequently diagnosed with urologic malignancy. Consequently, periodic follow-up may be warranted.6,20 AUA best practice guidelines suggest repeating urinalysis, voided urinary cytology, and blood pressure measurements at 6, 12, 24, and 36 months after the initial diagnosis of hematuria.9 However, several recent studies question the cost-effectiveness of such a follow-up schedule in asymptomatic low-risk individuals owing to the very low incidence of positive findings.1,21 Follow-up imaging studies and cystoscopy may be warranted in patients with persistent hematuria, in whom there is a high index of suspicion for significant underlying disease.
SUMMARY

Hematuria can be a sign of serious underlying genitourinary disease. Prompt and systematic evaluation of the genitourinary system should be initiated in the primary care setting and nephrologic or urologic consultations should be obtained, based on the suspected cause of hematuria. Methodical assessment of the upper and lower urinary tracts, as recommended by the AUA best practice guidelines (see Fig. 1), is paramount for the early detection and successful management of the underlying genitourinary disease.11
REFERENCES

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