What is the differential diagnosis for red blood cells (RBCs) in urine, also known as hematuria?

Differential Diagnosis for Red Blood Cells in Urine

The differential diagnosis for hematuria encompasses urologic malignancies, infections, stones, glomerular diseases, and systemic conditions—with the specific cause highly dependent on patient age, smoking history, and whether the RBCs are dysmorphic (glomerular) or isomorphic (non-glomerular). 1

Urologic/Non-Glomerular Causes

Malignancies (High Priority in Risk Assessment)

• Bladder cancer (transitional cell carcinoma)—most frequently diagnosed malignancy in hematuria evaluations, particularly in patients >60 years, smokers, or those with occupational chemical exposure 1, 2
• Renal cell carcinoma—detected on multiphasic CT urography in intermediate- and high-risk patients 2
• Upper tract urothelial carcinoma (UTUC)—requires upper tract imaging for detection 1
• Prostate cancer—consideration in elderly males with concurrent lower urinary tract symptoms 2

Benign Urologic Conditions

• Urolithiasis (kidney/ureteral stones)—causes painful hematuria, identified on CT urography 1, 2
• Benign prostatic hyperplasia (BPH)—common in men but does not exclude concurrent malignancy; gross hematuria from BPH must be proven prostatic in origin 2
• Urinary tract infection (UTI)—common cause of both microscopic and macroscopic hematuria; requires urine culture before antibiotics 1, 2
• Trauma—to kidneys or lower urinary tract; gross hematuria after trauma requires contrast-enhanced CT 2

Renal/Glomerular Causes

Primary Glomerular Diseases

• IgA nephropathy—frequent cause of asymptomatic microhematuria with episodic gross hematuria 1, 3
• Post-infectious glomerulonephritis—suggested by tea-colored urine, complement consumption (low C3/C4) 2, 4
• Alport syndrome—hereditary nephritis with associated hearing loss and ocular abnormalities 1, 2
• Thin basement membrane nephropathy—autosomal dominant condition causing persistent microscopic hematuria 2

Secondary Glomerular Diseases

• Lupus nephritis—requires ANA testing and nephrology referral 2, 4
• ANCA-associated vasculitis—rapidly progressive; requires urgent autoimmune serologies 4
• Other vasculitides—may present with systemic symptoms 2

Other Renal Parenchymal Diseases

• Interstitial nephritis—drug-induced or analgesic nephropathy 2
• Renal papillary necrosis—associated with sickle cell disease 2

Systemic and Metabolic Causes

• Hypercalciuria—metabolic abnormality causing microscopic hematuria, may progress to nephrolithiasis 2
• Hyperuricosuria—similar presentation to hypercalciuria 2
• Nutcracker syndrome—left renal vein compression causing hematuria with variable proteinuria 2

Hematologic and Coagulation Disorders

• Coagulopathies (hemophilia)—bleeding disorders causing hematuria 1
• Sickle cell disease—causes hematuria via renal papillary necrosis; may show sickle cells in urinary sediment 2, 5
• Anticoagulation/antiplatelet therapy—does NOT cause hematuria but may unmask underlying pathology; evaluation should proceed regardless 1, 2

Benign/Transient Causes

• Vigorous exercise—causes transient hematuria that resolves with rest 2
• Menstrual contamination—in women; requires repeat clean-catch specimen 48 hours after cessation of bleeding 2, 6
• Sexual activity—benign cause requiring exclusion before extensive workup 6

Distinguishing Features for Diagnostic Approach

Glomerular vs. Non-Glomerular Hematuria

• Glomerular bleeding indicators: >80% dysmorphic RBCs, RBC casts (pathognomonic), tea-colored urine, significant proteinuria (protein-to-creatinine ratio >0.2), hypertension 2, 4, 7
• Non-glomerular bleeding indicators: >80% isomorphic (normal) RBCs, bright red blood, clots, associated with irritative voiding symptoms 2, 7

Critical Red Flags Requiring Urgent Evaluation

• Gross hematuria—30-40% association with malignancy; requires urgent urologic referral even if self-limited 2, 4
• RBC casts or >80% dysmorphic RBCs—suggests rapidly progressive glomerulonephritis requiring immediate nephrology referral 4
• Concurrent proteinuria and hematuria—strongly suggests glomerular origin; urgent evaluation to exclude RPGN 4
• Declining renal function with hematuria—requires immediate nephrology consultation 4

Age-Specific Considerations

• Children: Glomerulonephritis and congenital anomalies most common; ultrasound preferred imaging modality 1, 2
• Adults >35-60 years: Malignancy becomes significant risk factor requiring complete urologic evaluation 2
• Elderly (>60 years): High-risk category; cystoscopy and CT urography recommended for most cases of microscopic hematuria 2

Common Pitfalls to Avoid

• Never attribute hematuria to anticoagulation alone—these medications unmask pathology but don't cause bleeding; full evaluation required 1, 2
• Don't rely on dipstick alone—65-99% specificity; requires microscopic confirmation of ≥3 RBCs/HPF 1, 2
• Don't ignore gross hematuria even if self-limited—requires complete urologic workup regardless of resolution 2, 4
• Don't skip evaluation in patients with identified benign causes—UTI or stones don't exclude concurrent malignancy in high-risk patients 2