What are the next steps for evaluating hematuria (blood in urine) without a urinary tract infection (UTI)?

Evaluation of Hematuria Without Infection

For hematuria without infection, you must first confirm true microscopic hematuria (≥3 RBCs per high-power field on microscopic examination), then pursue complete urologic evaluation with upper tract imaging (CT urography) and cystoscopy to exclude malignancy, particularly in patients with risk factors such as age >35-40 years, smoking history, or gross hematuria. 1, 2

Initial Confirmation and Exclusion of Benign Causes

Before initiating any workup, confirm that dipstick-positive results represent true hematuria:

• Verify with microscopic urinalysis showing ≥3 RBCs per high-power field on at least two of three properly collected clean-catch midstream specimens 1, 2
• Dipstick testing has limited specificity (65-99%) and can produce false positives from myoglobin, hemoglobin, or other substances 2, 3

Exclude transient benign causes before proceeding:

• Menstrual contamination in women (repeat specimen timing) 2
• Vigorous exercise (transient hematuria resolves within 48-72 hours) 2
• Recent sexual activity or trauma 3
• Viral illness 3

Critical pitfall: Do NOT attribute hematuria to anticoagulation or antiplatelet therapy—these medications may unmask underlying pathology but do not cause hematuria themselves, and evaluation should proceed regardless 1, 2

Risk Stratification for Malignancy

The approach differs dramatically based on whether hematuria is gross or microscopic:

Gross (Visible) Hematuria

• Carries 30-40% risk of malignancy 2, 4
• Requires urgent urologic referral for all patients, even if self-limited 1, 4
• Painless gross hematuria has stronger association with cancer than hematuria with flank pain (which may suggest stones) 4

Microscopic Hematuria

• Carries 2.6-4% overall malignancy risk, but up to 25.8% in high-risk populations 2, 5
• Risk stratification based on:
  • Age: Women <60 years (low risk), ≥60 years (intermediate); Men <40 years (low risk), 40-59 years (intermediate), ≥60 years (high risk) 2
  • Smoking: Never/<10 pack-years (low), 10-30 pack-years (intermediate), >30 pack-years (high) 2
  • Degree of hematuria: 3-10 RBCs/HPF (low risk), higher counts increase risk 2
  • Occupational exposures: Benzenes, aromatic amines, chemicals/dyes (high risk) 1, 2, 4
  • History of gross hematuria (high risk even if currently microscopic) 1, 2

Distinguishing Glomerular from Non-Glomerular Sources

This distinction determines whether nephrology or urology referral is primary:

Features Suggesting Glomerular (Renal) Origin:

• Tea-colored or cola-colored urine 2, 4
• >80% dysmorphic RBCs on urinary sediment examination 2, 4
• Red blood cell casts (pathognomonic for glomerular disease) 2, 4
• Significant proteinuria (protein-to-creatinine ratio >0.2 g/g) 2, 4
• Elevated serum creatinine or declining renal function 2, 4
• Hypertension in conjunction with hematuria 2, 4

Features Suggesting Non-Glomerular (Urologic) Origin:

• Normal-shaped (isomorphic) RBCs (>80% normal) 2, 4
• Minimal or no proteinuria 2, 4
• Normal serum creatinine 2, 4
• Irritative voiding symptoms (urgency, frequency, dysuria) without infection 2
• Clots in urine (glomerular bleeding does not produce clots) 2

Complete Urologic Evaluation for Non-Glomerular Hematuria

For patients with confirmed microscopic hematuria without glomerular features and with risk factors, or any patient with gross hematuria:

Upper Tract Imaging:

• CT urography (multiphasic) is the preferred imaging modality for detecting renal cell carcinoma, transitional cell carcinoma, and urolithiasis 2, 4, 3
• MR urography is an alternative if CT is contraindicated (renal insufficiency, contrast allergy) 4
• Renal ultrasound alone is insufficient for comprehensive upper tract evaluation due to limited sensitivity for small masses 2
• Traditional intravenous urography (IVU) remains acceptable but has limited sensitivity 2

Radiation consideration: CT urography carries nontrivial radiation exposure with greatest carcinogenesis risk in younger patients, where malignancy probability is lowest—this supports risk-stratified approaches 1

Lower Tract Evaluation:

• Cystoscopy is mandatory for all patients with gross hematuria and for microscopic hematuria patients with risk factors 1, 2, 3
• Flexible cystoscopy causes less pain with equivalent or superior diagnostic accuracy compared to rigid cystoscopy 2
• Age thresholds: Generally recommended for all patients ≥40 years, and younger patients with risk factors 3

Laboratory Testing:

• Complete urinalysis with microscopic sediment examination 2, 3
• Serum creatinine, BUN, complete metabolic panel to assess renal function 2, 4, 3
• Urine culture if infection suspected (preferably before antibiotics) 2, 4
• Do NOT obtain urinary cytology or urine-based molecular markers in the initial evaluation—these are not recommended by current guidelines 1

Nephrology Evaluation for Glomerular Hematuria

If features suggest glomerular origin, nephrology referral is indicated:

Additional Laboratory Testing:

• Spot urine protein-to-creatinine ratio (normal <0.2 g/g) 2
• Complement levels (C3, C4) to evaluate for post-infectious glomerulonephritis or lupus nephritis 2
• Antinuclear antibody (ANA) and ANCA testing if vasculitis suspected 2
• Urine calcium-to-creatinine ratio if hypercalciuria suspected 2

Imaging:

• Renal ultrasound with Doppler to evaluate kidney size, echogenicity, structural abnormalities 2
• Enlarged echogenic kidneys suggest acute glomerulonephritis 2
• Ultrasound can diagnose Nutcracker syndrome (left renal vein compression) 2

Indications for Nephrology Referral:

• Persistent significant proteinuria (protein-to-creatinine ratio >0.2 for three specimens) 2
• Presence of red cell casts or >80% dysmorphic RBCs 2
• Elevated creatinine or declining renal function 2
• Hypertension with hematuria and proteinuria 2

Follow-Up Protocol for Negative Initial Evaluation

If complete urologic workup is negative but hematuria persists:

• Repeat urinalysis at 6,12,24, and 36 months 2, 4, 3
• Monitor blood pressure at each visit 2, 4, 3
• Consider nephrology referral if hematuria persists with development of hypertension, proteinuria, or evidence of glomerular bleeding 2, 4, 3

Triggers for Immediate Re-evaluation:

• Recurrent gross hematuria 4
• Significant increase in degree of microscopic hematuria 2
• New urologic symptoms (irritative voiding symptoms, flank pain) 2
• Development of hypertension, proteinuria, or glomerular bleeding features 2

Special Populations and Considerations

Elderly Patients (≥60-80 years):

• Malignancy risk is significantly elevated 2, 4
• Urine cytology recommended in all patients ≥80 years due to high transitional cell carcinoma risk 4
• Full urologic evaluation mandatory even with identified benign causes (e.g., BPH) 2, 4
• Benign prostatic hyperplasia can cause hematuria but does not exclude concurrent malignancy 2

Patients on Anticoagulation:

• Pursue full evaluation regardless of anticoagulation or antiplatelet therapy 1, 2
• These medications may unmask underlying pathology requiring investigation 2

Low-Risk Patients:

• Young patients (<35-40 years) without risk factors and with identified benign cause may not require extensive imaging 2
• However, maintain low threshold for complete evaluation if any concerning features develop 2

Common Pitfalls to Avoid

• Never ignore gross hematuria, even if self-limited—30-40% malignancy risk mandates urgent urologic referral 1, 4
• Never defer evaluation due to anticoagulation/antiplatelet therapy 1, 2
• Never rely on dipstick alone—confirm with microscopic examination showing ≥3 RBCs/HPF 1, 2
• Never use screening urinalysis for cancer detection in asymptomatic adults 1
• Never obtain urine cytology as part of initial evaluation—not recommended by current guidelines 1
• Never assume renal ultrasound alone is sufficient for upper tract evaluation 2
• Never attribute hematuria to medications (including Cialis/tadalafil) without thorough investigation 2