Differential Diagnosis of Hematuria
Primary Classification
Hematuria must first be classified as either gross (visible) or microscopic, as this fundamentally determines malignancy risk and urgency of evaluation. Gross hematuria carries a 30-40% malignancy risk, while microscopic hematuria has only a 2.6-4% risk 1.
Gross Hematuria Etiologies
- Malignancy (30-40% of cases): Bladder cancer (most common), renal cell carcinoma, upper tract urothelial carcinoma 1
- Urolithiasis: Kidney or ureteral stones causing mucosal trauma 1
- Infection: Severe cystitis, pyelonephritis, prostatitis 1
- Trauma: Blunt or penetrating renal injury, bladder injury with pelvic fractures 1
- Benign prostatic hyperplasia: Particularly in older men 1
- Coagulopathy or anticoagulation: Though this alone does NOT explain hematuria and requires full evaluation 1
Microscopic Hematuria Etiologies
Non-Glomerular (Urologic) Causes
- Malignancy: Bladder cancer, renal cell carcinoma, upper tract urothelial carcinoma (lower risk than gross hematuria) 1
- Urolithiasis: Small stones causing microscopic bleeding 1
- Infection: Urinary tract infection, prostatitis 1
- Benign prostatic hyperplasia: Common in men over 40 1
- Anatomic abnormalities: Polycystic kidney disease, medullary sponge kidney 1
Glomerular (Nephrologic) Causes
- IgA nephropathy: Most common cause of isolated glomerular hematuria 2
- Thin basement membrane disease (benign familial hematuria) 2
- Alport syndrome: Hereditary nephritis with hearing loss 2
- Post-infectious glomerulonephritis: Following streptococcal infection 3
- Lupus nephritis, vasculitis, other systemic diseases 3
Risk Stratification for Malignancy
The 2025 AUA/SUFU guideline provides a critical risk stratification system that determines evaluation intensity 1:
High Risk (1.3-6.3% malignancy risk)
- Men ≥60 years 1
- >25 RBC/HPF on urinalysis 1
- Smoking history >30 pack-years 1
- History of gross hematuria with 3-25 RBC/HPF on repeat urinalysis 1
Intermediate Risk (0.2-3.1% malignancy risk)
Low/Negligible Risk (0-0.4% malignancy risk)
Distinguishing Glomerular from Non-Glomerular Sources
Features Suggesting Glomerular Origin
- Dysmorphic RBCs (>80% of RBCs) on phase-contrast microscopy 2, 3
- Red blood cell casts (pathognomonic for glomerular disease) 2
- Significant proteinuria (>300 mg/day or protein/creatinine ratio >0.3) 2
- Elevated serum creatinine suggesting renal parenchymal disease 1, 2
- Hypertension in the absence of other causes 2
Features Suggesting Non-Glomerular Origin
- Normal-shaped (isomorphic) RBCs 2
- Minimal or no proteinuria 2
- Normal serum creatinine 2
- Presence of clots (glomerular bleeding does not clot) 4
Additional Differential Considerations
Benign Transient Causes (Exclude Before Extensive Workup)
- Vigorous exercise: Resolves within 48-72 hours of rest 1
- Menstruation: Ensure proper specimen collection 1
- Sexual intercourse: Recent trauma 1
- Viral illness: Transient glomerular inflammation 3
Medication-Induced Hematuria
- Cyclophosphamide: Hemorrhagic cystitis 3
- Anticoagulants/antiplatelets: Do NOT explain hematuria; full evaluation still required 1
- NSAIDs: Analgesic nephropathy, papillary necrosis 3
Occupational/Environmental Exposures
- Aromatic amines, benzene chemicals: Dye, rubber, leather industries (bladder cancer risk) 1
- Aristolochic acid: Herbal supplements (upper tract urothelial carcinoma) 1
Critical Pitfalls to Avoid
- Never attribute hematuria solely to anticoagulation or antiplatelet therapy without complete evaluation 1
- Do not delay urologic referral for gross hematuria even if bleeding resolves spontaneously 2, 5
- Do not use urine cytology or molecular markers (NMP22, BTA stat) in initial evaluation of asymptomatic microscopic hematuria 1
- Recognize that significant renal injuries can occur with microscopic hematuria in trauma patients; mechanism of injury matters more than degree of hematuria 1
- Isolated microscopic hematuria in children without trauma, infection, or concerning features rarely requires imaging 1