What is the most likely diagnosis?A 40-year-old male with no past medical history presents to the clinic to establish care. He reports that he had a prior urinalysis that revealed blood as an incidental finding. The urinalysis was done as a standard screening test by his former employer. He denies ever seeing any blood in his urine and denies any voiding difficulties, dysuria, sexual dysfunction, or any history or risk factors for sexually transmitted diseases. His review of systems is otherwise negative. He has smoked a half-pack of cigarettes per day for the past 10 years and exercises by jogging 15 minutes and lightweight training daily. On examination, his vital signs are normal and the entire physical examination is unremarkable. A complete blood count (CBC) and a chemistry panel (electrolytes, blood urea nitrogen, and creatinine) are normal. The results of a urinalysis done in your office are: specific gravity, 1.015; pH 5.5; leukocyte esterase, negative; nitrites, negative; white blood cell count (WBC), 0; red blood cell count (RBC), 4 to 5 per high-power field (HPF).
What is the most likely diagnosis?
How would you approach this patient?
What is the workup and plan for this patient?
What are the concerns and how would you counsel the patient?
Summary: A 40-year-old male smoker is found incidentally to have red blood cells in his urine sample on a urinalysis.
• Current diagnosis: Asymptomatic microscopic hematuria.
• Initial approach: Repeat the urinalysis, assess for risk factors, image the upper and lower urinary tract.
• Workup and plan: Rule out infection by performing a urine culture; evaluate for malignancy by imaging of the upper urinary tract, cystoscopy, and voided cytology.
• Concerns and counseling: The primary concern is to rule out malignancy, including renal cell carcinoma and transitional cell carcinoma. Counsel the patient on the importance of an appropriate workup, but reassure the patient about the low prevalence of the condition.
1. Learn about the significance of microscopic hematuria.
2. Learn an evidence-based approach to workup asymptomatic microscopic hematuria.
3. Be familiar with recommendations for follow-up on patients with hematuria after a negative workup.
This patient has asymptomatic microscopic hematuria, as opposed to gross hematuria. Although he is asymptomatic, this patient deserves a thorough workup in order to determine an etiology, if possible, and to rule out malignancy.
The patient’s history should be reviewed with specific questions to determine any risks for sexually transmitted diseases (STDs), occupational exposures to chemicals, strenuous exercise, drugs, medications, and herbal/nutritional supplements. The workup should begin with a repeat urinalysis. If the condition persists, the patient should have imaging studies of both the upper and lower urinary tract. The upper tract can be imaged by either an intravenous pyelogram (IVP) or computed tomography (CT) scan. The lower tract is most commonly evaluated by cystoscopy, an endoscopic procedure. Urine should also be sent for cytology and culture. Urologic consultation should be requested if the workup reveals an abnormality that cannot be treated in a primary care office or if the condition persists. Inform the patient that a complete workup is necessary to evaluate for the presence of conditions such as infections or tumors, but he should be reassured that the incidence of cancer presenting as asymptomatic microscopic hematuria is low.
GROSS HEMATURIA: The presence of enough blood in a urine sample to be visible to the naked eye
LOWER URINARY TRACT: The urinary bladder and urethra
MICROSCOPIC HEMATURIA: The presence of three or more red blood cells per HPF on two or more properly collected urinalyses
UPPER URINARY TRACT: The kidneys and ureters
Hematuria is divided into glomerular, renal (nonglomerular), and urologic etiologies. Glomerular hematuria typically is associated with significant proteinuria, erythrocyte casts, and dysmorphic RBCs. Renal (nonglomerular) hematuria is secondary to tubulointerstitial, renovascular, and metabolic disorders. Like glomerular hematuria, it often is associated with significant proteinuria; however, there are no associated dysmorphic RBCs or erythrocyte casts. Urologic causes of hematuria include tumors, calculi, infections, trauma, and benign prostatic hyperplasia (BPH). Urologic hematuria is distinguished from other etiologies by the absence of proteinuria, dysmorphic RBCs, and erythrocyte casts.
Hematuria in adults should first be defined as gross hematuria or microscopic hematuria. Gross hematuria denotes that the patient is able to visualize blood in his voided specimen. Patients most often describe their urine as having a reddish or brownish color. Patients are commonly concerned about malignancy or kidney stones. In contrast, microscopic hematuria is usually asymptomatic and often discovered incidentally. Although a thorough workup of microscopic hematuria is advocated, many authorities do not recommend routine screening for hematuria.
Clinically significant microscopic hematuria is defined as 3 or more RBCs per HPF on microscopic evaluation of urinary sediment from two of three properly collected urinalysis specimens. The initial determination of microscopic hematuria should be based on microscopic examination of urinary sediment from a freshly voided, early morning, clean-catch, midstream urine specimen. Urine must be refrigerated if it cannot be examined promptly, as delays of more than 2 hours between collection and examination often cause unreliable results.
Hematuria can be measured quantitatively by any of the following methods:
• Determination of the number of red blood cells per milliliter of urine excreted (chamber count)
• Direct examination of the centrifuged urinary sediment (sediment count)
• Indirect examination of the urine by dipstick (the simplest way to detect microscopic hematuria).
Given the limited specificity of the dipstick method (65%-99% for 2-5 RBCs per high-power microscopic field), the initial finding of hematuria by the dipstick method should be confirmed by microscopic evaluation of urinary sediment. The limited specificity is due to the fact that the urine dipstick lacks the ability to distinguish RBCs from myoglobin or hemoglobin.
Despite the recommendation that two positive urinalyses are needed prior to workup, it is important to consider the individual patient’s risk factors. If a patient has significant risk factors, even one properly collected urine specimen with 1 to 2 RBCs is sufficient to warrant a workup. Risk factors include smoking, occupational exposure to chemicals or dyes (benzenes or aromatic amines), history of gross hematuria, older than age 40 years, history of urologic disorder or disease, history of irritative voiding symptoms, history of urinary tract infection, analgesic abuse, or history of pelvic irradiation.
The prevalence of asymptomatic hematuria is roughly 0.20% in the adult population in the United States. There are a myriad of possible causes; risk factors should guide the specific workup for the individual patient. Although some elements of the workup are standard for everyone, other more detailed and expensive tests can be deferred for those at low risk. The presence of significant proteinuria, red cell casts, renal insufficiency, or a predominance of dysmorphic red blood cells in the urine should prompt an evaluation for renal parenchymal disease or referral to a nephrolo-gist. In general, glomerular bleeding is associated with more than 80% dysmorphic red blood cells, whereas lower urinary tract bleeding is associated with more than 80% normal red blood cells.
Evaluation of the urinary sediment can allow for the diagnosis of patients with renal parenchymal disease. This analysis will often also allow for distinction between glomerular disease and interstitial nephritis. The presence of red cell casts and dysmorphic red blood cells is suggestive of renal glomerular disease. Interstitial nephritis, often caused by analgesics or other drugs, is suggested by the presence of eosinophils in the urine.
A complete evaluation for microscopic hematuria starts with a detailed history and physical examination, appropriate laboratory testing (including urinary cytology), and imaging of the upper and lower urinary tract. In all patients, the urinalysis should be repeated. If the repeat urinalysis is negative and the patient remains asymptomatic, no further workup is required for low-risk patients. Transient microscopic hematuria can be caused by sexual intercourse, heavy exercise, a recent digital prostate examination, or contamination by menses. However, if the hematuria persists, a full workup is warranted regardless of a benign history or physical examination. The repeat urinalysis should be done after avoidance of any potential confounders such as menses, medications, exercise, drugs, and nutritional/herbal products. Exercise-induced hematuria usually resolves spontaneously in 72 hours in the absence of other coexisting conditions. In addition, careful attention should be taken in women to ensure the blood is not from the vaginal or rectal areas. In men, one should also exclude local trauma to the foreskin. If in doubt, a catheterized specimen should be obtained, taking care not to induce trauma during the procedure.
The laboratory studies should start with urinalysis with microscopy and evaluation of centrifuged urinary sediment. The urine should be examined for number of RBCs per HPF, dysmorphic RBCs, and presence of casts and eosinophils. Urinary tract infection (UTI) should be ruled out by urine culture. If an infection is present, it should be appropriately treated and the urinalysis repeated in 6 weeks. If the hematuria resolves with treatment of the UTI, no further workup is needed.
A serum creatinine should also be obtained to assess renal function, with comparison to old records if available. If the laboratory evaluation reveals elevated creati-nine or red cell casts, workup should focus on renal parenchymal disease and possible etiologies such as hypertension, diabetes, or autoimmune diseases. Renal biopsy may be appropriate for certain individuals. Patients with risk factors should also undergo cytologic evaluation of the urine to assess for transitional cell carcinoma. Although voided urine cytology may not pick up low-grade carcinoma, it is fairly reliable for high-grade lesions, especially if repeated.
Numerous options exist for imaging of the upper urinary tract. Despite many studies comparing the radiographic methods, there are no evidence-based guidelines on which modality is most efficient. An IVP is x-ray imaging of the upper urinary tract after the administration of an intravenous contrast dye. It is a widely available and relatively low-cost procedure, but it can miss small renal masses and may not distinguish solid from cystic lesions. Ultrasonography is also widely available and does not require the use of contrast dye but also may miss small lesions. CT scanning has a high sensitivity and specificity for detecting masses, renal stones, renal or perirenal infections, and obstruction. The CT scan should be initially performed as a noncontrast study to detect calculi, and then a contrast study should be obtained. Multidetector CT urography combines the benefits of CT scanning and IVP; however, it is associated with high doses of radiation and should not be used in pregnant women. Some centers restrict multidetector CT urography to patients older than 40 or patients younger than 40 with known risk factors for genitourinary malignancies. Both CT scanning and IVP may lead to nephropathy caused by IV contrast dye. Premedication with N-acetylcysteine or IV sodium bicarbonate may be used to reduce the risk of contrast nephropathy. In patients with renal insufficiency or who are at high risk of contrast nephropathy, a retrograde pyelography combined with a renal ultrasound may be an option. Retrograde pyelography is an invasive procedure in which a catheter is placed in the bladder and dye injected up the ureters to the kidneys. There is little risk of contrast nephropathy because no contrast dye is given IV.
The lower urinary tract should be examined for transitional cell carcinoma by cystoscopy performed by an urologist. In the absence of risk factors in selected patients with a negative history, examination, laboratory workup, and upper tract imaging, cystoscopy may be deferred or individualized at the discretion of the treating physician.
In patients with a thorough but negative workup, the American Urological Association recommends follow-up blood pressure measurements, urinalyses, and voided urine cytologic studies at 6, 12, 24, and 36 months. The reason for the regular follow-up is to assess for the possibility of an underlying lesion, despite a low likelihood of there being one. If the workup remains negative for 36 months and the patient continues to be asymptomatic, no further follow-up is recommended. However, if the patient develops gross hematuria, voiding difficulties, pain, or any abnormal cytology, immediate urologic reevaluation and urologic consultation is warranted. Patients who develop hypertension, proteinuria, glomerular casts, or abnormal renal function should be referred to a nephrologist for consultation.
14.1 A 24-year-old male bodybuilder with no significant medical history presents with gross hematuria. He was told by his trainer that exercise can induce hematuria and that this is nothing to worry about. He comes to you for a second opinion. Which of the following is the most appropriate management at this time?
A. Urinalysis now. If no blood is noted, repeat in 6 months.
B. Urinalysis and urine culture now. If they are normal, no other workup is needed.
C. Urinalysis after 72 hours of no exercise. If no blood in urine, then diagnose exercise-induced hematuria.
D. Urinalysis, urine culture, and imaging of upper urinary tract by CT scanning.
14.2 A 78-year-old man with multiple medical problems presents with dysuria and is found to have microscopic hematuria. His examination is only positive for a very tender and boggy prostate. Which of the following is the best next step?
A. Stat urology referral.
B. Treat the prostatitis with 1 month of antibiotics and reevaluate the patient with a follow-up urinalysis and culture posttreatment.
C. Obtain an IVP followed by cystoscopy.
D. Obtain a CT of the abdomen and pelvis, followed by cystoscopy.
14.3 A 45-year-old woman with a history of cancer, currently receiving radiation therapy, presents as a new patient. On a routine urinalysis, you discover 2 RBCs per HPF, 15 to 20 WBCs per HPF, nitrites, and leukocyte esterase. Which of the following is the next most appropriate step?
A. Repeat a clean-catch midstream specimen, send for culture, and treat the UTI. Repeat urinalysis after the UTI treatment.
B. Treat the UTI and also refer the patient for an IVP and cystoscopy.
C. Check urine for cytology.
D. Inform the patient that the urinalysis results are a result of the radiation treatment and no further workup is needed.
14.1 D. Gross hematuria always deserves a full workup. Although exercise-induced hematuria resolves in 72 hours, gross hematuria, especially in a person with risk factors, must have a thorough evaluation.
14.2 B. A tender/boggy prostate alludes to the diagnosis of prostatitis. Reevaluation should be done after adequate treatment of the prostatitis. If the hematuria persists following treatment, further workup is necessary.
14.3 A. True microscopic hematuria is the presence of 3 or more RBCs per HPF in a midstream clean-catch specimen after exclusion of a UTI. If there is evidence of an UTI, it should be cultured, treated, and urinalysis repeated after treatment.
Hematuria in adults should always be evaluated. If no source is found on a thorough initial workup, patients should be followed for at least 3 years to monitor for an underlying condition.
Patients should be thoroughly instructed in the proper technique for a “clean-catch” urine sample. This will reduce the number of false-positive findings.
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