Hematuria Without Infection: Differential Diagnosis and Evaluation
When hematuria persists after excluding urinary tract infection, the differential diagnosis must be systematically approached by first distinguishing between gross versus microscopic hematuria, then determining whether the source is glomerular versus non-glomerular, as this fundamentally changes both the differential diagnosis and the specialist referral pathway. 1
Immediate Risk Stratification
Gross (visible) hematuria carries a 30-40% risk of malignancy and mandates urgent urologic referral, even if self-limited. 2, 1, 3 This is a critical clinical pearl that is frequently missed in practice—self-limited gross hematuria provides false reassurance but carries an odds ratio of 7.2 for urologic cancer. 2
Microscopic hematuria (≥3 RBCs/HPF) has a lower but still significant malignancy risk of 2.6-4%, increasing to 25.8% in high-risk populations. 1, 4
Major Differential Diagnosis Categories
Urologic (Non-Glomerular) Causes
Malignancy is the most critical diagnosis to exclude:
- Bladder cancer (most common urologic malignancy causing hematuria) 1
- Renal cell carcinoma 1
- Upper tract urothelial carcinoma 1
- Prostate cancer 1
Benign urologic conditions:
- Benign prostatic hyperplasia (BPH) in men 1, 5
- Urolithiasis (kidney/ureteral stones)—typically presents with painful hematuria 1
- Urinary tract trauma 1
- Urethral stricture or urethritis 5
Renal/Glomerular Causes
Primary glomerular diseases:
- IgA nephropathy (most common primary glomerulonephritis worldwide) 1
- Post-infectious glomerulonephritis 1
- Thin basement membrane nephropathy (benign familial hematuria) 1
- Alport syndrome (hereditary nephritis with hearing loss) 1
Secondary glomerular diseases:
Other renal parenchymal causes:
- Polycystic kidney disease 1
- Renal infarction 1
- Papillary necrosis (especially in sickle cell disease) 1
- Interstitial nephritis (drug-induced) 1
Systemic and Metabolic Causes
- Coagulopathies (hemophilia, von Willebrand disease) 1
- Sickle cell disease/trait 1
- Hypercalciuria (can cause microscopic hematuria and predispose to stones) 1
- Hyperuricosuria 1
- Nutcracker syndrome (left renal vein compression) 1
Transient/Benign Causes to Exclude First
- Vigorous exercise (transient, resolves within 48-72 hours) 2, 1
- Menstrual contamination in women 2, 1
- Recent sexual activity 6
- Recent instrumentation or catheterization 6
Critical Diagnostic Algorithm
Step 1: Confirm True Hematuria
Dipstick positivity MUST be confirmed with microscopic examination showing ≥3 RBCs/HPF before initiating any workup. 2, 1 Dipstick has only 65-99% specificity and can be falsely positive from myoglobinuria, hemoglobinuria, or concentrated urine. 6
Obtain at least 2 of 3 properly collected clean-catch midstream specimens showing ≥3 RBCs/HPF. 6
Step 2: Determine Glomerular vs. Non-Glomerular Source
Glomerular hematuria is suggested by:
- >80% dysmorphic RBCs on phase-contrast microscopy 1
- Red blood cell casts (pathognomonic for glomerular disease) 1
- Significant proteinuria (protein-to-creatinine ratio >0.2 g/g) 1
- Tea-colored or cola-colored urine 1
- Elevated serum creatinine 1
Non-glomerular hematuria is suggested by:
- >80% normal-shaped (isomorphic) RBCs 1
- Minimal or no proteinuria 1, 3
- Normal renal function 3
- Bright red blood or clots 1
Step 3: Risk Stratification for Malignancy
High-risk features requiring full urologic evaluation: 1, 6
- Age ≥60 years (men) or ≥60 years (women) 1
- Smoking history >30 pack-years 1
- Occupational exposure to chemicals/dyes (benzenes, aromatic amines) 1, 6
- History of gross hematuria (even if self-limited) 2, 1
- History of pelvic irradiation 6
- Chronic analgesic abuse 6
- History of urologic disorder or malignancy 6
Intermediate risk: Age 40-59 (men), smoking 10-30 pack-years, or 10-25 RBCs/HPF 1
Low risk: Age <40 (men) or <60 (women), never smoker or <10 pack-years, 3-10 RBCs/HPF 1
Complete Evaluation Pathway
For Non-Glomerular (Urologic) Hematuria:
Laboratory evaluation:
- Urine culture (to definitively exclude infection) 2
- Serum creatinine and BUN 1, 6
- Urine cytology (in patients ≥40 years or with risk factors for transitional cell carcinoma) 3, 6
Imaging:
- CT urography is the gold standard for upper tract evaluation 1, 3, 6
- Alternative: MR urography if CT contraindicated 3
- Renal ultrasound with retrograde pyelography if cross-sectional imaging not feasible 3
Cystoscopy:
- Mandatory for all patients ≥40 years 6
- Mandatory for patients <40 years with risk factors 6
- Mandatory for ALL patients with gross hematuria regardless of age 3, 6
For Glomerular Hematuria:
Laboratory evaluation:
- Complete metabolic panel (creatinine, BUN, albumin) 1
- Spot urine protein-to-creatinine ratio 1
- Complement levels (C3, C4) for post-infectious GN or lupus nephritis 1
- ANA and ANCA if vasculitis suspected 1
- Anti-GBM antibodies if Goodpasture syndrome suspected 1
Imaging:
- Renal ultrasound to assess kidney size, echogenicity, and structural abnormalities 1
Nephrology referral indicated for: 1, 6
- Persistent significant proteinuria (protein-to-creatinine ratio >0.2) 1
- Red cell casts or >80% dysmorphic RBCs 1, 6
- Elevated creatinine or declining renal function 1, 6
- Hypertension with hematuria and proteinuria 1, 6
Common Pitfalls to Avoid
Do NOT attribute hematuria to anticoagulation or antiplatelet therapy. These medications may unmask underlying pathology but do not cause hematuria—full evaluation is still required. 2, 3
Do NOT delay urologic referral for gross hematuria, even if bleeding stops. Self-limited gross hematuria still carries high malignancy risk. 2, 3
Do NOT skip microscopic confirmation of dipstick-positive hematuria. This leads to unnecessary referrals for "pseudohematuria." 2
Do NOT assume infection is the cause without culture confirmation. If infection is confirmed, repeat urinalysis after treatment to document resolution—persistent hematuria requires full evaluation. 2
Follow-Up Protocol for Negative Initial Evaluation
If complete urologic and nephrologic evaluation is negative, repeat urinalysis at 6,12,24, and 36 months. 3, 6
Monitor blood pressure at each visit. 3, 6
Immediate re-evaluation is required if: 3