Primary Care Corner with Geoffrey Modest MD: Hematuria Evaluation

By Dr. Geoffrey Modest 

The Am College of Physicians just released an “advice for high-value care” regarding the assessment and workup of hematuria (see doi:10.7326/M15-1496​)​. Their points:

• Though there are no recommendations to support performing hematuria screening (the USPSTF gives it an “I”, or insufficient evidence, rating), millions of patients get routine urine dipsticks and microscopic exams (though many of these tests may be done for other reasons as well, given the multitude of evaluations on a single dipstick). But 44-77% of primary care physicians have been endorsing the use of urinalysis in routine practice, though the % is decreasing over time.
• Any episode of gross hematuria deserves more urologic attention, since the pretest probability of cancer or a clinically significant condition is high (>10-25%), vs asymptomatic microscopic hematuria–AMH (0.5-5.0%, but up to 20% in high-risk groups), though the prevalence of AMH is pretty high (0.9-18.0% of the adult population) large population-based case-control study of healthy adults found no difference in cancer incidence between those with and without dipstick-positive hematuria, with a sensitivity of screening of 2.9% and positive predictive value of 0.2-0.5% for cancer, undermining the rationale for screening
• Most urologic societies recommend a microscopic exam if the urine dipstick is positive for blood, from a clean-catch midstream urine, with a positive finding being at least 3 RBCs/high-powered field [the Am Urological Assn (AUA) used to say there needed to be confirmation in 2 of 3 specimens, though now even 1 warrants further workup]
• The AUA has a lower age threshold (35 years old) vs other societies (40-60 yo) as a target for further workup. the AUA suggests workup at any age if high risk (male sex; past/current smoking; occupational exposure such as chimney sweeps, nurses, waiters, aluminum/ship/petroleum workers, exposure to aromatic amines as in tobacco/dye/rubber/leather workers/hairdressers/printers; history of gross hematuria; irritative voiding symptoms of frequency/urgency; chronic UTIs; exposure to carcinogenic chemotherapy; chronic indwelling foreign body) — not sure what to make of this, since probably 70% of the population qualifies, e.g. being male and history of smoking.  and ??nurses, waiters are at high risk?
• Further evaluation includes CT urography per the AUA, though the Canadian and Dutch guidelines promote ultrasound to decrease radiation exposure
• The AUA still recommends complete urologic evaluation even in the presence of high-probability of underlying renal disorders (dysmorphic red cells, proteinuria, cellular casts, CKD, hypertension)
• Also AUA suggests performing the full workup even if the patient is on antiplatelet or anticoagulant therapy
• They do not suggest urinary cytologic evaluation or using the FDA-approved bladder cancer detection tests (lots of false positives and negatives)
• Harms of AMH evaluation:
  • Anxiety, discomfort of cystoscopy, the uncommon complications of cystoscopy (infection in up to 3.7%, sepsis, urethral stricture); complications of CT urography (contrast nephropathy in 2% and up to 20% in higher risk patients with heart failure or CKD), cost
  • In terms of radiation exposure from CT urography, there is considerable variability depending on the scanner/imaging protocol, but is typically 20-30 mSv (with some centers in the 7-10 range, but some up to the 90 mSv range…). The National Research Council concluded that 10 mSv may have increased risk of cancer. The higher doses are projected to create 4 cancers per 1000 patients (see, for prior blogs in https://stg-blogs.bmj.com/bmjebmspotlight/category/radiation/on the issue of radiation exposure.)

Their formal suggestions for “high-value care”:

• Make sure to ask patients about gross hematuria as part of the review of systems
• Do not do routine urinalysis in healthy, asymptomatic patients with primary intent to screen for cancer
• If urinalysis is done and results positive for heme, do a microscopic exam of the urine, with 3 or more RBCs/hpf being abnormal
• Refer for urologic evaluation if gross hematuria
• Consider referral for cystoscopy and imaging in patients with AMH in the absence of a demonstrable benign cause [(e.g. menstruation, viral illness, vigorous exercise, UTI, etc), then repeat the urinalysis after that potential cause is no longer present (though some urology societies recommend up to 3 repeated urinalyses to confirm absence of a more serious cause)]
• Pursue hematuria evaluation even if the patient is on anti-platelet or anti-coagulant therapy
• Don’t get  urine cytology or use the newer tests for bladder cancer markers

So, a few points:

• The change in the AUA guidelines to treat any single urinalysis finding hematuria as a basis for further workup (similar to any positive stool guaiac) is appropriate and a bit late, since there were studies I saw perhaps 25 years ago confirming that both renal and bladder cancers can produce intermittent hematuria. For this reason, I personally do perform 3 repeat urinalyses if there may be a confounding and benign cause (vigorous exercise, UTI, etc.), and especially so if there are risk factors for cancer as above (though working as a waiter or nurse was not on my list….). And it is important to understand the importance of gross hematuria, though it may be very intermittent and both the patient and clinician may not pay much attention to that (though beware of eating beets, or taking rifampin as a cause of red-colored urine). One study did find that in patients referred to urology for AMH, 20% had gross hematuria within the past 6 months on further questioning, without that having been ascertained by the primary care clinician.
• Up to 1/3 of urine dipsticks are positive for heme but have negative microscopic exams (likely heme-positive from free hemoglobin, as from hemolysis, or myoglobin, or even from semen/sperm being present in the urine). And it makes sense that a microscopic exam be done on the same urine specimen when there is a heme-positive dipstick exam.
• Primary care clinicians often under-refer to urology for AMH, even in situations of high cancer risk (lots of the risk factors above, including occupational, or even with gross hematuria). And the concern is that a detected bladder cancer is usually quite curable if early/superficial, and much less so when invasive. A SEER (surveillance, epidemiology and end-results)-Medicare dataset found that delaying the diagnosis of bladder cancer >9 months after a claim for hematuria had a much higher mortality than if < 3 months (median cancer-specific survival of 50.9 months vs 70.9 months (see Cancer, 2010: 116: 5235). And this delay in referral seems to be much greater in women
• These guidelines do not discuss the most rational approach, in my opinion. It seems reasonable, though untested, to do a renal evaluation first. If there is evidence of a renal cause for hematuria (e.g., some combination of dysmorphic red cells, casts, proteinuria, renal dysfunction, abnormal radiologic assessment), I tend to pursue the renal workup at that point and consider referral to a nephrologist if the etiology remains unclear, there is progressive disease, the imaging study is concerning for a serious underlying pathology, etc. I am not convinced that everyone in this category needs cystoscopy…  But if the renal imaging is normal and there are no compelling reasons to consider a renal etiology, I absolutely support referral for cystoscopy and have occasionally picked up early transitional cell carcinomas. So, I am not sure that their algorithm to check “renal function testing, cystoscopy, and imaging” is appropriate. I should note that the 2012 AUA guidelines (go to URL: https://www.auanet.org/education/guidelines/asymptomatic-microhematuria.cfm​ ) does comment that even if a renal cause is likely because of these findings (they tend to focus too much on the less-reliable marker of RBC dysmorphism), “the presence of renal disease disease does not exclude a urologic process and evaluation should include assessment for urologic pathology”. Seems to me that Occam’s razor needs a sharpening….