Based on the 2020 AUA Guidelines on microscopic hematuria.
Background
Hematuria has 14 recognised causes, split into malignant and non-oncologic:
- Malignancy: kidney, renal pelvis/ureter, bladder, prostate, urethra.
- Non-oncologic: infection, inflammation, stones, benign prostatic hyperplasia (BPH), benign urinary-tract tumour, congenital or acquired anatomic abnormalities, urethral strictures and diverticula, trauma, and recent urological procedures/catheterization.
The overall risk of urinary-tract malignancy in patients with hematuria is ~10% — 13% with gross hematuria and 1–3% with microscopic hematuria (MH), the vast majority of which are bladder cancers. Prevalence of MH among healthy volunteers is 2–30%, depending on the population evaluated.
Urine dipstick detects the peroxidase activity of hemoglobin using benzidine. Causes of a false-positive dipstick (5): myoglobinuria, dehydration, exercise, menstrual blood, and povidone-iodine (betadine). Urine may also appear red from ingestion of certain foods and drugs.
Definition of MH: ≥3 RBCs per high-power field on microscopic examination of a single, properly collected specimen. (CUA guidelines recommend 2 positive samples.) A positive dipstick merits microscopic examination of the sediment but does not warrant full evaluation unless microscopy confirms ≥3 RBC/HPF. If <3 RBC/HPF but true MH is still suspected, repeat microscopic testing may be reasonable after assessing patient risk and preference.
Sample collection:
- A random midstream clean-catch collection is sufficient for most initial evaluations; patients should discard the initial 10 mL of voided urine.
- If a significant number of squamous cells are present, contamination is possible — repeat collection or catheterization should be considered. Catheterization may be necessary in some patients (e.g. obese females; those with a non-intact urinary tract, a Foley or suprapubic catheter, or who use intermittent catheterization).
- Women with concurrent menstruation should be re-evaluated after it ceases, or undergo catheterization to confirm the blood is truly in the urine rather than vaginal contamination.
- Do not examine specimens collected immediately after prolonged recumbency (first morning void) or after vigorous physical or sexual activity.
Risk Stratification
Factors to consider (5): age, smoking, urinalysis, risk factors for urothelial cancer, and gross hematuria.
| Factor | Low (meets all) | Intermediate (any) | High (any) |
|---|---|---|---|
| Age | Females <50; males <40 | Females 50–59; males 40–59 | Females or males ≥60 |
| Smoking | Never, or <10 pack-years | 10–30 pack-years | >30 pack-years |
| Urinalysis | 3–10 RBC/HPF on a single UA | 11–25 RBC/HPF on a single UA, or a low-risk patient with no prior evaluation and 3–10 RBC/HPF on repeat UA | >25 RBC/HPF on a single UA |
| Risk factors for urothelial cancer | None | Yes | — |
| Gross hematuria | — | — | Yes |
Recommended Investigations by Risk
- History and physical exam — all patients.
- Laboratory — serum creatinine and GFR for all patients; urine cytology and other markers are not recommended.
- Upper-tract imaging — renal US for intermediate-risk; CT urography for high-risk; optional for low-risk; performed regardless of risk if there is a family history of RCC or a genetic renal tumour syndrome.
- Cystoscopy — intermediate- and high-risk; optional for low-risk.
- Low-risk patients who initially decline cystoscopy or upper-tract imaging should undergo repeat UA within 6 months.
History and Physical Exam
Assess the degree and persistence of hematuria, any history of gross hematuria, and irritative lower-urinary-tract symptoms.
Risk factors for malignancy (8): age, male sex, smoking, prior pelvic radiation therapy, prior cyclophosphamide/ifosfamide chemotherapy, family history of urothelial cancer or Lynch syndrome, occupational exposure to benzene chemicals or aromatic amines (e.g. rubber, petrochemicals, dyes), and a chronic indwelling foreign body in the urinary tract.
Physical exam: general (including blood pressure measurement) and genitourinary. In females, examination of the external genitalia, introitus, and periurethral tissue may identify urethral or other gynecologic pathology explaining the MH.
Other Causes of MH
- Medical renal disease — proteinuria, dysmorphic RBCs, cellular casts, or renal insufficiency on microscopy may indicate medical renal disease. Refer for nephrologic evaluation if suspected, but still perform risk-based urologic evaluation.
- Gynecologic and non-malignant genitourinary causes — repeat urinalysis after the cause resolves. MH may take several weeks to a few months to clear after treating a gynecologic/non-malignant cause or a UTI; waiting ≥3 weeks after resolution and ≤3 months is appropriate. If MH persists or the etiology cannot be identified, perform risk-based urologic evaluation.
- Causes that persist and may not require intervention (3): enlarged prostates with friable surface vessels; Randall's plaques and non-obstructing stones; and women with pelvic organ prolapse or vaginal atrophy. Use careful judgment and shared decision-making, informed by the patient's malignancy risk factors.
- MH in patients taking anticoagulants requires the same evaluation regardless of the type or level of anticoagulation therapy.
Laboratory
Serum creatinine and GFR (not required in CUA guidelines). Goals of renal-function assessment (2): identify kidney disease (abnormal function warrants establishing the etiology of renal dysfunction, related to or independent of the hematuria), and guide the choice of imaging modality should it be needed. Renal dysfunction increases the risk of contrast or gadolinium studies and must be considered when selecting diagnostic procedures.
Urinary markers — urine cytology and urine markers (NMP22, BTA-stat, UroVysion FISH) are not recommended in routine MH evaluation (CUA guidelines recommend cytology). Cytology may be useful in persistent MH following a negative work-up, or in those with other risk factors for carcinoma in situ.
Imaging
Goals of upper-tract imaging (2): identify malignancies of the renal parenchyma and upper-tract urothelium, and identify actionable non-malignant diagnoses of the kidney, collecting system, and ureters (e.g. stones).
- CT urography — advantages: excellent delineation of the excretory urinary tract, very sensitive for stones, readily identifies renal cortical lesions, and provides extra-urinary information. Disadvantages: generally more expensive than renal US, and involves ionizing radiation and IV contrast.
- Renal US — advantages: relatively less expensive, no ionizing radiation, and reasonable discrimination for cortical lesions. Disadvantages: image quality depends on the operator and the patient's body habitus, and lower sensitivity for urothelial lesions, small solid renal lesions, and kidney stones.
- By risk: renal US for intermediate-risk and CT urography for high-risk (CUA guidelines recommend US).
- Contraindications to contrast-enhanced CT: chronic kidney disease, and allergy to iodine-based contrast. If CT is contraindicated, consider MR urography; if both CT and MR urography are contraindicated, consider retrograde pyelography with non-contrast axial imaging, or US.
- In persistent or recurrent MH previously evaluated with renal US, consider additional urinary-tract imaging. With a family history of RCC or a known genetic renal tumour syndrome, perform upper-tract imaging regardless of risk category. For MH in pregnancy, obtain renal US, with multiphasic CT or MR urography considered after delivery.
Cystoscopy
Recommended for intermediate- and high-risk patients (CUA guidelines say >40 years). White-light cystoscopy remains the standard for MH evaluation; the benefit of blue-light cystoscopy here is unknown.
For low-risk patients, the likelihood of upper-tract malignancy is exceedingly low. Two options: (1) cystoscopy with renal ultrasound, or (2) repeat UA within 6 months (to limit delay in diagnosing a curable malignancy). Low-risk patients who initially declined cystoscopy or upper-tract imaging and are then found to have microhematuria on repeat testing should be reclassified as intermediate- or high-risk and undergo cystoscopy and upper-tract imaging accordingly. In one large study, patients with persistent MH on repeat testing had a higher malignancy rate than those with negative repeat testing.
Negative Evaluation
- Obtain a repeat urinalysis within 12 months. Patients with a negative follow-up UA may be discharged from further hematuria evaluation, given the very low risk of malignancy.
- For a prior negative evaluation with persistent or recurrent microhematuria at repeat urinalysis, engage in shared decision-making regarding the need for additional evaluation.
- For a prior negative evaluation who develop gross hematuria, a significant increase in the degree of microhematuria, or new urologic symptoms, initiate further evaluation.