What is the correct order of workup for a patient presenting with hematuria?

Hematuria Workup Algorithm for USMLE Step 2

The correct order of workup for hematuria follows a systematic approach: (1) confirm true hematuria with microscopic urinalysis showing ≥3 RBCs/HPF, (2) perform history/physical/labs to distinguish glomerular from non-glomerular sources, (3) conduct risk stratification for malignancy, and (4) proceed with appropriate imaging and cystoscopy based on risk category. 1, 2

Step 1: Confirm True Hematuria

• Verify microscopic hematuria by demonstrating ≥3 red blood cells per high-power field on microscopic examination of at least two of three properly collected clean-catch midstream urine specimens 1, 2
• Dipstick positivity alone is insufficient—specificity is only 65-99% and produces false positives from myoglobin, hemoglobin, menstruation, or vigorous exercise 1, 2
• Critical pitfall: 0-2 RBCs/HPF is within normal limits and does not warrant urologic workup 1

Step 2: Initial Clinical Assessment

History and Physical Examination

• Assess malignancy risk factors: age >35 years (especially >60 years), male sex, smoking history (quantify pack-years), occupational exposure to benzenes/aromatic amines/chemicals/dyes 1, 2
• Identify benign causes to exclude: urinary tract infection, recent vigorous exercise, menstruation (repeat UA 48 hours after cessation), recent urologic procedures, trauma 1, 3
• Evaluate for glomerular disease indicators: tea-colored urine, recent upper respiratory infection, family history of kidney disease, hearing loss (Alport syndrome) 1, 2
• Document urologic symptoms: irritative voiding symptoms, flank pain, dysuria 1
• Measure blood pressure at initial visit 2

Laboratory Evaluation

• Complete urinalysis with microscopic sediment examination to assess RBC morphology: >80% dysmorphic RBCs or presence of red cell casts indicates glomerular source 1, 2
• Serum creatinine and complete metabolic panel (BUN, albumin, total protein) to evaluate renal function 1, 2
• Quantify proteinuria using spot urine protein-to-creatinine ratio (normal <0.2 g/g)—significant proteinuria strongly suggests glomerular disease 1, 2
• Urine culture if infection suspected (preferably before antibiotics) 4, 1

Step 3: Determine Source (Glomerular vs. Non-Glomerular)

Glomerular Source Indicators → Nephrology Referral

• 80% dysmorphic RBCs or red cell casts (pathognomonic for glomerular disease) 1, 2

• Significant proteinuria (protein-to-creatinine ratio >0.2) with hematuria 1, 2
• Elevated creatinine or declining renal function 1
• Additional workup for glomerular source: complement levels (C3, C4), ANA, ANCA if vasculitis suspected, renal ultrasound to assess kidney size/echogenicity 1

Non-Glomerular Source → Urologic Evaluation

• 80% normal (eumorphic) RBCs suggests lower urinary tract bleeding 1

• Proceed to risk stratification for malignancy 2

Step 4: Risk Stratification for Malignancy (Non-Glomerular Hematuria)

Use the 2025 AUA/SUFU risk stratification system 2:

Low Risk (0%-0.4% malignancy risk)

• Women <60 years, men <40 years
• Never smoker or <10 pack-years
• 3-10 RBCs/HPF
• Workup: Renal ultrasound may be sufficient; cystoscopy optional 2

Intermediate Risk (0.2%-3.1% malignancy risk)

• Women ≥60 years, men 40-59 years
• 10-30 pack-years smoking history
• 11-25 RBCs/HPF
• Workup: Cystoscopy + upper tract imaging (CT urography preferred) 2

High Risk (1.3%-6.3% malignancy risk)

• Men ≥60 years

• 30 pack-years smoking history

• 25 RBCs/HPF

• History of gross hematuria
• Occupational chemical exposure
• Workup: Mandatory cystoscopy + CT urography + voided urine cytology 1, 2

Step 5: Imaging and Endoscopic Evaluation

Upper Tract Imaging

• Multiphasic CT urography is the preferred modality for detecting renal cell carcinoma, transitional cell carcinoma, and urolithiasis in intermediate- and high-risk patients 4, 1, 2
• Renal ultrasound alone is insufficient for comprehensive upper tract evaluation 1
• In children, ultrasound is preferred to assess kidney anatomy before potential renal biopsy 1

Lower Tract Evaluation

• Flexible cystoscopy is mandatory for intermediate- and high-risk patients to evaluate for bladder transitional cell carcinoma (most frequently diagnosed malignancy in hematuria) 1, 2
• Cystoscopy causes less pain than rigid cystoscopy with equivalent diagnostic accuracy 1

Urine Cytology

• Perform in high-risk patients to detect high-grade urothelial cancers and carcinoma in situ 1, 2

Step 6: Follow-Up Protocol

If Initial Workup Negative

• Repeat urinalysis at 6,12,24, and 36 months with blood pressure monitoring at each visit 1, 2
• Immediate re-evaluation warranted if: gross hematuria develops, significant increase in microscopic hematuria, new urologic symptoms, development of hypertension/proteinuria/glomerular bleeding 1, 2

Nephrology Referral Indications

• Persistent hematuria with hypertension, proteinuria, or evidence of glomerular bleeding 1, 2
• Persistent significant proteinuria (protein-to-creatinine ratio >0.2 for three specimens) 1
• Red cell casts or >80% dysmorphic RBCs 1

Special Considerations

Gross Hematuria

• 30-40% association with malignancy—requires urgent urologic referral even if self-limited 1
• Never ignore gross hematuria regardless of potential benign causes 1

Anticoagulation Therapy

• Not a reason to defer evaluation—anticoagulants may unmask underlying pathology but do not cause hematuria 1
• Proceed with full workup as indicated by risk stratification 1

Benign Prostatic Hyperplasia

• BPH can cause hematuria but does not exclude concurrent malignancy 1
• Gross hematuria attributed to BPH must be proven through appropriate evaluation 1