For urology, hematuria usually means a tumor or a stone; for nephrology, hematuria is more often considered kidney disease. Tumors and kidney disease are completely different at every step, from diagnosis to treatment. So, how should asymptomatic microscopic hematuria be considered?
Case summary
The patient was a male, 42 years old, admitted to the hospital with positive urinalysis hematuria (+), no proteinuria, no carnal hematuria, no lower urinary tract symptoms, no symptoms suggestive of renal calculi, and no systemic symptoms. The patient had a history of smoking (quit), no history of related diseases, occupational disease or family history, no prescription/over-the-counter medications, and no nutritional supplements. Blood pressure is 136/88 mmHg, physical examination is unremarkable, blood creatinine is 95 μmol/L, and estimated glomerular filtration rate (eGFR) is 80 mL/min/1.73 m2.
What should be the next step?
The convenience of multiple test urine test strips has led to the inadvertent screening of asymptomatic microscopic hematuria. Population screening for microscopic hematuria is currently only available in Japan; there is no national screening program in other countries because the risks and costs far outweigh the possible benefits.
Once asymptomatic microscopic hematuria is detected, guidelines in the UK and US recommend screening for the presence of urological tumors, as well as potentially progressive renal disease. However, these recommendations are based on evidence from observational studies and vary by specialty. These guidelines can be considered more conservative than reasonable.
Symptomatic patients
During the consultation, patients should be asked if they have ever had meatus hematuria, back pain, or painful urination. The presence of these symptoms cannot be considered asymptomatic microscopic hematuria. Microscopic hematuria is the best predictor of urologic tumors – the reported tumor detection rate is 8-25%. If there is painful urination, pus or nitrites on urinalysis suggestive of symptomatic urinary tract infection, the infection should be treated first.
Recurrent urinary tract infections are one of the characteristic manifestations of bladder cancer, but the infection must be treated before cystoscopy. Urinalysis should be repeated at the end of appropriate antibiotic therapy. If persistent microscopic hematuria is present after treatment, the examination is the same as asymptomatic microscopic hematuria.
Asymptomatic patients
In asymptomatic patients, no microscopic examination is necessary to confirm or exclude hematuria. The incidence of asymptomatic microscopic hematuria in individual screening is 2-13%. Urinalysis has a high sensitivity (97%) and moderate specificity (75%) for detecting hematuria compared to the gold standard, the fresh urine microscopic cell count. Fresh urine with no red blood cells found under phase contrast microscopy is the “gold standard” for determining a false positive urine test for hematuria. If erythrocyte tubular or heterogeneous erythrocytes are found, nephropathy is highly suspected.
However, red blood cells are easily lysed during storage, and phase contrast microscopy is rarely used during examination, and conventional microbiology microscopy does not easily detect red blood cells, so a false negative microscopy result is likely for a positive urine test. A urine test with erythrocytes/hemoglobin ≥1+ or ≥3 erythrocytes/mL microscopically (equivalent to ≥3 erythrocytes/high magnification field) can be considered a positive result.
Repeat urinalysis
Microscopic hematuria is often seen in physiological situations, so urine red blood cells should be retested after one week. Two positive urine tests out of three may confirm the diagnosis of persistent microscopic hematuria. Hematuria cannot be simply assumed to be caused by anticoagulants or antiplatelet agents.
Patients diagnosed with asymptomatic microscopic hematuria
Medical history and physical examination
Consultation should include questions about risk factors for urologic tumors (including smoking, cyclophosphamide use, and exposure to chemicals used in the manufacture of leather products, dyes, and rubber). Family history and physical examination may suggest the presence of hereditary kidney disease, such as polycystic kidney disease or Alport syndrome.
Further tests
Blood creatinine to assess renal function (eGFR) and random urine albumin/creatinine ratio. In a subset of patients, the presence of sickle cell is also checked. For most urologic tumors, the examination usually relies on cystoscopy rather than imaging. The results of imaging alone are not reliable and therefore should not be used alone. Current evidence does not support screening for the presence of asymptomatic small kidney stones.
Urine cytology and tumor markers should not be used as routine tests. In patients with asymptomatic microscopic hematuria, there is little evidence of final confirmation of tumor with these tests, and the reported sensitivity varies widely from 0 to 100%.
When should I be referred?
After a diagnosis of asymptomatic microscopic hematuria is confirmed, patients have three routes of
Referral to nephrology
Referral to urology
Continued observation in a primary care facility
Table -1 lists the key points of the referral criteria recommended by the UK and US guidelines and the National Institute for Health and Clinical Excellence (NICE) for the treatment of asymptomatic microscopic haematuria.
Table -1 Referral criteria for asymptomatic microscopic hematuria
Referral to nephrology
Referral to nephrology has a greater benefit for patients whose diagnosis and treatment can change the course of the disease, or who must be treated with renal replacement therapy. Examination of proteinuria, hypertension, and the rate of renal decompensation is more valuable than assessment of renal function alone when assessing prognosis. However, in elderly patients, hypertension is a common concomitant condition and therefore is of little significance in identifying the presence of glomerulogenic hemorrhage. Renal biopsy can provide a histologic diagnosis but can lead to a number of risks, such as life-threatening bleeding.
The benefit of treatment of chronic progressive kidney disease (control of blood pressure, restriction of salt intake and blockade of the renin-angiotensin-aldosterone system to reduce proteinuria) is not very relevant to histology. In most cases, the treatment of asymptomatic microscopic hematuria cases with diagnostic findings on renal biopsy, such as IgA nephropathy or thin basement membrane nephropathy, is usually not specific. Even when treatment is effective, patients with proteinuria or progressive hyperalgesia have limited benefit.
Referral to urology
Current UK and US guidelines recommend referral to urology to rule out tumors in patients who smoke or are older than 35-40 years. Do not routinely refer patients to both nephrology and urology. Urology usually performs a structured workup including consultation, cystoscopy, and imaging of the upper urinary tract. Observational cohort studies have shown a 2.6% prevalence of urologic tumors in the asymptomatic microscopic hematuria population.
An analysis of a case-control study matched by age and sex showed that the prevalence of microscopic hematuria was 313/4915 (6.4%) in patients with bladder cancer compared to 60/20718 (0.3%) in controls. In the text, it can be inferred that the positive predictive value for bladder cancer in patients over 60 years of age was 1.6% compared to 0.8% in patients aged 40-59 years.
However, the way urine testing was performed may not have been consistent in the case and control groups; a proportion of patients with symptomatic bladder cancer may have also undergone urine testing. The correlation between positive predictive values and incidental microscopic hematuria in truly asymptomatic patients is limited. A case-control study showed no significant difference in tumor incidence among patients with/without hematuria in a population undergoing a healthy physical examination. These data suggest that a positive urine test for hematuria has a sensitivity of only 3% for tumor diagnosis and a positive predictive value of 0.2%.
If a patient’s asymptomatic microscopic hematuria is caused by a urologic tumor, early diagnosis may well improve the prognosis compared to waiting to develop carnal hematuria. If the patient is at risk for recurrent bladder cancer, the lag in the development of sarcoid hematuria is only less than 3 months behind the detection of asymptomatic microscopic hematuria, but it is not clear whether this lag is consistent for first bladder or kidney cancer.
Screening often causes patient anxiety, cystoscopy can cause a 2% risk of urinary tract infection, and imaging increases ionizing radiation exposure. There is no high-quality evidence that screening for asymptomatic microscopic hematuria for the presence of a urinary tract tumor improves prognosis better than screening for carnal hematuria alone.
International guidelines are usually based on the findings of systematic reviews of observational studies that aim to guide screening protocols for patients at high risk for tumors. In an observational cohort study, the protocol was based on the most recent US guidelines and found a tumor incidence of less than 0.5% in those younger than 50 years. Clearly, the younger the age, the lower the incidence rate.
Current U.S. guidelines suggest that smokers should be screened earlier than nonsmokers and that CT urography should be used instead of ultrasound. CT urography may prevent missing rare migratory cell carcinomas that are confined to the upper urinary tract. However, whether this benefit warrants radiation exposure requires further study.
All current guidelines in urology are based on single cohort observational studies with great heterogeneity and often expert consensus rather than strong evidence. Because there is uncertainty in the consultation, the best approach is to develop patient decision aids (PDAs) to help patients choose each step of the examination based on their values and preferences. Patients who are not willing to take risks and are at high risk for disease will choose more tests, while others will choose watchful waiting.
Recent studies have shown that 81-92% of patients are tested for tumors even though the probability of a diagnosis is 1%, although this is also related to the specific tumor and the acceptability of the test. This illustrates the importance of allowing patients to make their own decisions about what tests to undergo. Patient decision aids can be updated by systematically reviewing the regression of patients who are screened according to current guidelines.
Continued observation at the primary care facility
The majority of patients with microscopic hematuria do not meet the above referral criteria. These patients can be considered to have glomerular-derived hemorrhage, so blood pressure, eGFR, and urinary albumin/creatinine ratio should be assessed annually in the primary care setting. Consult nephrology if proteinuria or decreased renal function is present (Table -1). Some patients who meet the criteria for referral to urology may also choose to remain in primary care for observation, especially if the individual risk of developing a tumor is clear.
Prognosis
This patient was referred to urology because he was over 40 years of age. The diagnosis of persistent microscopic hematuria was confirmed 3 years later, without new symptoms, proteinuria, hypertension or renal impairment.
Patients with asymptomatic microscopic hematuria have a 1% chance of missing a urologic tumor, but this does not mean that a urologic examination is needed before the development of visual hematuria. Similar diagnoses are made for IgA nephropathy and thin basement membrane nephropathy.
Variants in the type IV collagen gene are the cause of thin basement membrane nephropathy, Alport syndrome, and other related conditions, and tests for this gene variant may become available in the next few years. Patients with persistent asymptomatic microscopic hematuria are nearly 20 times more likely to develop end-stage renal failure than patients without hematuria, but the absolute risk is not high (34 vs 2 per 100,000 people * year).
Persistent microscopic hematuria requires annual urinalysis for the presence of hematuria, urinary albumin/creatinine ratio, eGFR, and monitoring of blood pressure as long as hematuria is still present.