Microscopic Hematuria (2020 AUA Guidelines)

See AUA Asymptomatic Microscopic Hematuria Guidelines 2016

See CUA Asymptomatic Microscopic Hematuria Guidelines 2008

Background

Causes of hematuria (14):
1. Malignancy:
  1. Kidney
  2. Renal pelvis/ureter
  3. Bladder
  4. Prostate
  5. Urethra
2. Non-oncologic
  1. Infection
  2. Inflammation
  3. Stones
  4. Benign prostatic hyperplasia (BPH)
  5. Benign tumor in urinary tract
  6. Congenital or acquired anatomic abnormalities
  7. Urethral strictures and diverticula
  8. Trauma
  9. Recent urological procedures/catheterization
Risk of urinary tract malignancy in patients with hematuria: 10%
- 13% for patients with gross hematuria and 1-3% among patients with microscopic hematuria (MH)
- Vast majority are bladder cancers
Prevalence of MH among healthy volunteers: 2-30% depending on the specific population evaluated.
Urine dipstick
- Detects the peroxidase activity of hemoglobin using benzidine
- Causes of false-positive dipstick (5):
  1. Myoglobinuria
  2. Dehydration
  3. Exercise
  4. Menstrual blood
  5. Povidone-iodine (betadine)
Urine may appear red in color from ingestion of certain foods and drugs
Definition of MH: ≥ 3 RBCs per high powered field on microscopic examination of a single properly collected, urinary specimen. (CUA Guidelines recommend 2 positive samples)
- For most initial evaluations, a random midstream clean-catch collection is sufficient.
  - Patients should discard the initial 10 mL of voided urine in order to collect the midstream void.
- If a significant number of squamous cells are present in the sample, contamination is possible and a repeat specimen collection or catheterization should be considered.
- Catheterization may be necessary in order to obtain an appropriate specimen in some patients such as obese female patients and patients with a non-intact urinary tract, a Foley catheter, a suprapubic catheter, or who use intermittent catheterization.
- Females with concurrent menstruation should be reevaluated after its cessation or should undergo catheterization to determine if the blood is in fact present in the urine or is only noted as a result of vaginal contamination.
- A positive dipstick merits microscopic examination of the urinary sediment, but does not warrant full evaluation unless microscopic evaluation confirms ≥3 RBC/HPF.
  - If <3 RBC/HPF but suspicious that the findings could reflect true MH, then repeat microscopic testing may be reasonable after assessing patient risk and preference.

Diagnosis and Evaluation

Risk stratification

Factors to consider (5):
1. Age
2. Smoking
3. Urinalysis
4. Risk factors for urothelial cancer
5. Gross hematuria

	Low (meets all criteria)	Intermediate (any of these criteria)	High (any of these criteria)
Age	Females age <50 years Males age <40 years	Females age 50-59 years Males age 40-59 years	Females or Males ≥60 years
Smoking	Never smoker OR <10 pack years	10-30 pack years	>30 pack years
UA	3-10 RBC/HPF on a single urinalysis	11-25 RBC/HPF on a single urinalysis OR Low-risk patient with no prior evaluation and 3-10 RBC/HPF on repeat urinalysis	>25 RBC/HPF on a single urinalysis
Risk factors for urothelial cancer (see below)	None	Yes
Gross hematuria			Yes

Recommended investigations based on risk stratification (4)
1. History and Physical Exam (all patients)
2. Laboratory: serum Cr and GFR (all patients); urine cytology or other markers are not recommended
3. Imaging: upper tract imaging (intermediate, high-risk, and if family history of RCC or other genetic renal tumor syndrome)
  - US for intermediate-risk
  - CT urography for high-risk
4. Cystoscopy (intermediate and high-risk)

History and Physical Exam

History
- Risk factors for malignancy (12):
  1. Age
  2. Male sex
  3. Smoking
  4. Degree of hematuria
  5. Persistence of hematuria
  6. History of gross hematuria
  7. Irritative lower urinary tract symptoms
  8. Prior pelvic radiation therapy
  9. Prior cyclophosphamide/ifosfamide chemotherapy
  10. Family history of urothelial cancer or Lynch Syndrome
  11. Occupational exposures to benzene chemicals or aromatic amines (e.g., rubber, petrochemicals, dyes)
  12. Chronic indwelling foreign body in the urinary tract
- Medical renal disease
  - Proteinuria, dysmorphic RBCs, cellular casts, or renal insufficiency on urine microscopy may be associated with medical renal disease, which can cause hematuria
    - If medical renal disease is suspected, refer patients for nephrologic evaluation. However, risk-based urologic evaluation should still be performed.
- Gynecologic and non-malignant genitourinary causes of MH
  - Repeat urinalysis following resolution of the gynecologic or non-malignant genitourinary cause.
    - MH may not resolve for several weeks to a few months following treatment of a gynecologic or non-malignant cause of MH, or treatment of a UTI; waiting ≥ 3 weeks after resolution of the non-malignant etiology and ≤ 3 months would be appropriate.
      - If MH persists or the etiology cannot be identified, perform risk-based urologic evaluation.
    - Causes of MH that persist and may not require intervention (3):
      1. Enlarged prostates and friable surface vessels
      2. Randall’s plaques and non-obstructing stones
      3. Women with pelvic organ prolapse or vaginal atrophy
      - In these cases, use careful judgment and shared decision-making to decide whether to pursue MH evaluation. Attention to the patient’s risk factors for urologic malignancy should inform these decisions.
- MH in patients who are taking anti-coagulants requires the same evaluation evaluation regardless of the type or level of anti-coagulation therapy
Physical examination
- Blood pressure measurement +/- genitourinary examination, as dictated by the history.
  - In females, examination of the external genitalia, introitus, and periurethral tissue may identify urethral pathology or other gynecologic pathology to explain the MH.

Laboratory

Serum creatinine and GFR (NOT required in CUA guidelines)
- Goals of renal function assessment in MH patients (2):
  1. Identify kidney disease
    - Abnormal renal function warrants evaluation to include establishing the etiology of renal dysfunction either as it relates to, or independent of, the cause of hematuria
  2. Guide the choice of imaging modality, should that be deemed necessary based on patient risk
  - - Renal dysfunction increases the risk of contrast or gadolinium radiologic studies and needs to be considered in the selection of these diagnostic procedures.
Urinary markers
- Urine cytology and urine markers (NMP22, BTA-stat, and UroVysion FISH) are NOT recommended as a part of the routine MH evaluation (CUA Guidelines recommend cytology)
- Urine cytology may be useful in patients with persistent MH following a negative work up or those with other risk factors for carcinoma in situ

Imaging

Goals of upper tract imaging in MH patients (2):
1. Identify malignancies of the renal parenchyma and upper tract urothelium
2. Identify actionable non-malignant diagnoses of the kidney, collecting system, and ureters (e.g. stones)
CT urography
- Advantages
  1. Excellent delineation of the excretory urinary tract
  2. Very sensitive for urinary stones
  3. Readily identifies renal cortical lesions
  4. Provides extra-urinary information as well
- Disadvantages
  1. Generally more expensive than renal US
  2. Involves ionizing radiation and intravenous contrast
Renal US
- Advantages
  1. Relatively less expensive
  2. Does not involve ionizing radiation
  3. Reasonable discrimination for cortical lesions
- Disadvantages
  1. Image quality is dependent on the operator and the patient’s body habitus
  2. Lower sensitivity for urothelial lesions, small solid renal lesions, and kidney stones
Recommended modality based on risk-stratification: (CUA Guidelines recommend US)
- US for intermediate-risk
- CT urography for high-risk
  - Contraindications to contrast-enhanced CT
    - Chronic kidney disease
    - Allergy to iodine-based contrast
  - If CT contraindicated, consider MR urography; if both CT and MR urography contraindicated, consider retrograde pyelography with non-contrast axial imaging or US
In patients with persistent or recurrent MH previously evaluated with renal US, consider additional imaging of the urinary tract
In patients with MH who have a family history of renal cell carcinoma or a known genetic renal tumor syndrome, upper tract imaging should be performed regardless of risk category.
For MH during pregnancy, obtain renal US with consideration of multiphasic CT or MR urography after delivery.

Cystoscopy

Recommended for intermediate- and high-risk (CUA Guidelines say >40)
White light cystoscopy (WLC) remains the standard for evaluation of MH
The benefit of blue light cystoscpy in the evaluation of MH remains unknown

Low-risk

The likelihood of upper tract malignancy is exceedingly low
Clinicians should discuss cystoscopy and imaging with renal ultrasound as options for evaluation, but should also review the option to repeat UA
- Repeat UA should be performed within 6 months in order to limit the delay in diagnosis of curable malignancy should an underlying cancer be present.
- Low-risk patients who initially elected not to undergo cystoscopy or upper tract imaging and who are found to have microhematuria on repeat urine testing should be reclassified as intermediate- or high-risk.
  - In such patients, clinicians should perform cystoscopy and upper tract imaging in accordance with recommendations for these risk strata.
  - In one large study, patients who had persistent MH on repeat urine testing had a higher rate of malignancy on subsequent evaluation as compared with those who had negative repeat urine testing

Negative evaluation

In patients with a negative hematuria 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 patients with a prior negative hematuria evaluation who have persistent or recurrent microhematuria at the time of repeat urinalysis, engage in shared decision-making regarding need for additional evaluation.
For patients with a prior negative hematuria evaluation who develop gross hematuria, significant increase in degree of microhematuria, or new urologic symptoms, clinicians should initiate further evaluation