Hematuria Case File

Hematuria Case File

Eugene C. Toy MD, Donald Briscoe, MD, FA  AFP, Bruce Britton, MD, Joel J. Heidelbaugh, MD, FA  AFP, FACG

Case 14

A 40-year-old man 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 (STDs). 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 [BUN], 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?

ANSWER TO CASE 14:

Hematuria

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 and possible reversible causes such as urinary tract infection (UTI), vigorous exercise or recent urologic procedure, perform renal function testing, and then depending on low or high risk of malignancy, perform additional imaging of lower and/or upper urinary tract.
• Workup and plan: Rule out infection by performing urine culture; obtain further history including exercise routine or recent urologic procedures; perform renal function testing to rule out renal disease. If all of this is negative, evaluate for malignancy by imaging of the upper urinary tract via computed tomography (CT) urography and the lower urinary tract via cystoscopy.
• 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.

ANALYSIS

Objectives

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.

Considerations

This patient has asymptomatic microscopic hematuria, as opposed to gross hematuria. The American Urological Association (AUA) defines significant microscopic hematuria as more than 3 RBCs per HPF on urinalysis with microscopy. Although he is asymptomatic, this patient deserves a thorough workup in order to determine an etiology, if possible, and to rule out malignancy. The management guidelines differ in the workup of microscopic hematuria with fewer than 3 RBCs per HPF versus more than 3 RBCs per HPF.

The patient's history should be reviewed with specific questions to determine any risks for STDs, occupational exposures to chemicals, strenuous exercise, drugs, medications, and herbal/nutritional supplements. For a result of fewer than 3 RBCs per HPF, a urine analysis (UA) should be repeated three times at 6-week intervals. If these are negative (consistently <3 RBCs per HPF ), the workup is complete and the patient should be reassured. For a primary result of more than 3 RBCs per HPF, a urine culture should be sent to evaluate for UTI. If a source is found, a repeat UA with microscopy should be done 6 weeks after the etiology has been resolved (for UTI or STD) or offending agent has been removed (exposure, strenuous exercise, medications, etc).

At this point if the condition persists, renal function testing should be done to evaluate for possible renal disease. This may include a basic metabolic panel to check for BUN and creatinine as well as glomerular filtration rate (GFR). If there are abnormalities in renal function testing, a nephrology referral should be generated immediately. If, however, no renal abnormalities are found at this point, or the patient has risk factors for malignancy, imaging with CT urography and cystoscopy should be done. Inform the patient that a complete workup is necessary to evaluate for the presence of conditions such as infections or tumors, since as many as 30% to 40% of people with gross hematuria and about 5% of those with microscopic hematuria are positive for malignancy.

Approach To:

Hematuria

DEFINITIONS

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 3 or more RBCs per HPF on two or more properly collected urinalyses

UPPER URINARY TRACT: The kidneys and ureters

CLINICAL APPROACH

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 malignancy is found in 5% of all patients with incidental asymptomatic microscopic hematuria, United States Preventive Services Task Force (USPSTF) currently does not recommend routine screening for bladder cancer in asymptomatic patients (Level I).

Clinically significant microscopic hematuria is defined as 3 or more RBCs per HPF on microscopic evaluation of urinary sediment from a properly collected specimen. The initial determination of microscopic hematuria should be based on microscopic examination of urinary sediment from a freshly voided, early-morning, dean-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 HPF), 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.

Because of the possibility of bladder cancer, the AUA recommends that a single positive result for hematuria on UA with microscopy warrants further workup. There are certain risk factors that are associated with a higher probability of bladder cancer that should be explored and should serve as an impetus for timely and efficient workup and referrals. Risk factors include smoking, occupational exposure to chemicals or dyes (benzenes or aromatic amines), history of gross hematuria, older than age 40, history of urologic disorder or disease, history of irritative voiding symptoms, history of UTI, analgesic abuse, or history of pelvic irradiation.

The prevalence of asymptomatic microscopic hematuria is roughly 2% to 31%. in the males over the age of 60. 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 RBCs in the urine should prompt an evaluation for renal parenchymal disease or referral to a nephrologist. 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

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. If the UA with microscopy is positive for significant microscopic hematuria, further history should be obtained to rule out benign causes such as menstruation, strenuous exercise, recent urologic procedure, medications, etc. If a probable cause is determined, UA with microscopy should be repeated after 6 weeks of discontinuation of the cause. 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, other urologic procedures, or contamination by menses. 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. 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 creatinine or red cell casts, workup should focus on renal parenchymal disease and possible etiologies such as hypertension, diabetes, or autoimmune diseases. Referral to a nephrologist should be considered. 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. Choice of imaging modality should take into account any contraindications the patient may have including renal insufficiency, contrast allergy, or pregnancy. CT urography (with and without IV contrast), given its high sensitivity and specificity for imaging upper urinary tract, should be the initial modality of choice unless a contraindication exists. Urine cytology and urine markers should only be used in patients with risk factors for bladder cancer as detailed earlier; these procedures are not a part of the routine evaluation of microscopic hematuria. The lower urinary tract should be examined

for transitional cell carcinoma by cystoscopy in all patients who are older than 35 years or who present with risk factors for lower urinary tract malignancies. In the absence of risk factors in selected patients with a negative history, examination, laboratory workup, and upper tract imaging, and those younger than 35 years, cystoscopy may be deferred or individualized at the discretion of the treating physician.

In patients with a thorough but negative workup, UA with microscopy should be repeated annually for 2 consecutive years. For those with persistent asymptomatic microscopic hematuria, the AUA recommends repeat evaluation within 3 to 5 years of the initial evaluation. For those with two consecutively negative results on annual UA with microscopy, workup can be stopped. 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.

COMPREHENSION QUESTIONS

14.1 A 60-year-old man with past medical history of BPH presents to you with gross hematuria for 1 day. He states this has never happened before and denies strenuous exercise. Upon further questioning he does reveal that 2 days ago he had a bladder catheterization to evaluate his postvoid residual. He denies smoking, family history of cancers, or chemical exposures. Which of the following is the most appropriate management at this time?

A. Counsel the patient on the high likelihood of gross hematuria after a urologic procedure and that this will likely subside. Let him know no test is required today.

B. Do a urine dipstick first. If positive then proceed to urinalysis with microscopy and have the patient return in a few weeks for a repeat UA with microscopy.

C. Discuss with the patient the high likelihood of malignancy with gross hematuria especially given his age and past history and recommend imaging upper and lower urinary tracts.

D. Tell him that he likely needs urine cytology today to rule out malignancy.

14.2 A 54-year-old postmenopausal woman with past medical history of hypertension is incidentally found to have significant microscopic hematuria on a UA that was done as part of her annual hypertension laboratory tests. She denies dysuria, gross hematuria, fevers, chills, and nausea/vomiting. Her physical examination is negative for suprapubic tenderness and flank pain. What would be the next best step in the management of this patient?

A. Repeat UA with microscopy in 3 months at her next follow-up visit for hypertension.

B. Perform a urine culture and if positive, treat immediately. Repeat UA posttreatment.

C. Order renal function testing to rule out medical renal disease as an etiology.

D. Repeat UA with microscopy in 6 weeks.

14.3 A 65-year-old man with past medical history of hypertension, coronary artery disease, chronic kidney disease (CKD), and a pacemaker presents to your office with complaint of"dark urine" for many weeks now. He states he has been evaluated by several other physicians who had done "several tests" that all came back negative. He states he has never had any imaging done and would like you to "take a look at what is going on in there:' Upon accessing his medical records you see that he has already had several UA with microscopy that were all positive for microscopic hematuria, renal function testing, which is significant for elevated BUN and creatinine and decreased GFR, and negative urine cultures. At this time, what would be the most appropriate imaging modality and management for this patient?

A. Counsel the patient against imaging at this time as any imaging may worsen his CKD.

B. Order magnetic resonance urography (MRU) as the patient is unable to undergo CT urography given his renal insufficiency, along with an urgent urology referral.

C. Order a combined renal ultrasound and retrograde pyelogram for maximum visualization of upper urinary tract, along with an urgent urology referral.

D. Order urine cytology and urine markers as these are the least invasive test of choice at this time.

ANSWERS

14.1 B. Although it is very likely that the patient's hematuria is secondary to the recent urologic procedure, it is not a good practice to simply assume the cause and not do appropriate initial evaluation for hematuria, like one would for any patient with that chief complaint. The initial step in this case would be to do a urine dipstick, which if positive in office, would warrant a UA with microscopy. If this shows 3 or more RBCs per HPF, one would immediately go to thorough workup. However, if UA with microscopy shows fewer than 3 RBCs per HPF, the patient should be asked to return in 6 weeks for a repeat. It is appropriate to discuss with the patient that his gross hematuria, given his lack of risk factors for malignancy, is most likely caused by the recent bladder catheterization; however, as stated earlier, this is not a reason to dismiss further evaluation. Since there is a probable cause for this patient's hematuria, one would not immediately begin workup to rule out malignancy. Certainly, if his gross hematuria continues after several weeks, it would be imperative to conduct further evaluation.

14.2 D. This patient does not have signs or symptoms of a UTI and additional workup looking for an infection is not going to change management, as asymptomatic bacteriuria need not be treated except in pregnancy. As per the current guidelines, this patient needs a repeat UA with microscopy in 6 weeks before beginning workup to rule out medical renal disease. A 3-month interval between repeat UA testing is not an appropriate interval.

14.3 C. This patient has two simultaneous contraindications to imaging modalities preferred in the workup of microscopic hematuria. Due to his renal insufficiency he should not get a CT urography, and due to his pacemaker, he should not undergo MRI/MRU. For this reason, the next best imaging modality would have to be done, a renal ultrasound, which when combined with a retrograde pyelogram would provide maximum information about the upper urinary tracts. This would have to be done with a concurrent urology referral. Urine cytology and urine markers, although noninvasive, are not currently recommended in the routine evaluation of microscopic hematuria.

CLINICAL PEARLS

⯈ 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.

⯈ In every case of a first-time microscopic hematuria, a repeat urinalysis with microscopy is required at 6-week interval before any other management is done.

REFERENCES

Cohen RA, Brown RS. Microscopic hematuria. N Engl] Med. 2003;348:2330-2338. 

Davis RJ, Jones S, Barocas DA, et al. Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline. 2012. American Urological Association. Available at: https:// www.auanet.org/ common/pdf/ education/ clinical-guidance/ Asymptomatic-Microhematuria.pdf. Accessed May 24, 2015. 

Grossfeld GD, Litwin MS, Wolf JS, et al. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy-part I: definition, detection, prevalence, and etiology. Urology. 2001;57( 4):599-603. 

Grossfeld GD, Litwin MS, Wolf JS Jr, et al. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy-part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology. 2001;57( 4 ):604-610. 

Lin J, Denker BM, Bradley M. Azotemia and urinary abnormalities. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, et al., eds. Harrison's Principles of Internal Medicine. 19th ed. New York, NY : McGraw-Hill Education; 2015. Available at: http://accessmedicine.mhmedical.com/. Accessed May 24, 2015. 

McDonald MM, Swagerty D, Wetzel L. Assessment of microscopic hematuria in adults. Am Fam Physician. 2006;73(10):1748-1754. 

O'Connor OJ, McSweeney SE, Maher MM. Imaging of hematuria. Radiol Clin North Am. 2008;46:113. 

Sharp VJ, Barnes KT, Erickson BA. Assessment of asymptomatic microscopic hematuria in adults. Am Fam Physician. 2013 Dec 1;88(11):747-754. 

Simerville JA, Maxted WC, Pahira JJ. Urinalysis: a comprehensive review. Am Fam Physician. 2005; 71(6):1153-1162.

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