What are the appropriate evaluation and treatment steps for a patient with hematuria (blood in urine), considering potential underlying conditions such as kidney disease, diabetes, or hypertension?

Evaluation and Management of Hematuria

Immediate Action: Confirm True Hematuria

Do not proceed with any urologic workup until you confirm microscopic hematuria with ≥3 red blood cells per high-power field on microscopic examination. 1, 2 Dipstick testing alone has limited specificity (65-99%) and produces false positives from myoglobin, hemoglobin, menstrual contamination, or vigorous exercise. 1, 2

• Obtain microscopic urinalysis on two of three properly collected clean-catch midstream specimens before initiating any evaluation 2, 3
• If only one specimen shows ≥3 RBCs/HPF but the patient has high-risk features (age >40 years, smoking history, occupational chemical exposure), proceed with full evaluation after a single positive specimen 2, 4

Exclude Benign and Transient Causes First

Before pursuing expensive imaging or invasive procedures, systematically rule out reversible causes:

• Menstruation: Repeat urinalysis 48 hours after cessation 2, 3
• Vigorous exercise: Repeat urinalysis 48 hours after rest 2, 3
• Sexual activity or minor trauma: Repeat urinalysis after 48 hours 3
• Urinary tract infection: Obtain urine culture before antibiotics, treat appropriately, then repeat urinalysis 6 weeks after treatment completion to confirm resolution 2, 3
• Viral illness: Repeat urinalysis after resolution 3

Critical pitfall: If hematuria persists after treating a UTI at the 6-week follow-up, you must proceed with full urologic evaluation—do not prescribe additional antibiotics. 2 Persistent hematuria despite appropriate antibiotic therapy effectively rules out simple infection and strongly suggests urologic malignancy. 2

Distinguish Glomerular from Non-Glomerular Sources

This distinction determines whether you refer to nephrology or urology:

Glomerular Indicators (Nephrology Referral)

• Dysmorphic RBCs >80% on phase-contrast microscopy 1, 2
• Red blood cell casts (pathognomonic for glomerular disease) 1, 2
• Significant proteinuria: protein-to-creatinine ratio >0.5 g/g (or >500 mg/24 hours), especially if persistent or increasing 1, 2
• Elevated serum creatinine or declining renal function 1, 2
• Tea-colored or cola-colored urine (suggests glomerular bleeding) 2
• Hypertension accompanying hematuria 2, 3

Non-Glomerular Indicators (Urology Referral)

• Normal-appearing RBCs >80% (doughnut-shaped) 1, 4
• Absence of casts 4
• Minimal or no proteinuria 4
• Normal renal function 4
• Bright red blood (suggests lower urinary tract) 2

Risk Stratification for Urologic Malignancy

All patients with gross hematuria require urgent urologic referral regardless of risk factors—gross hematuria carries a 30-40% malignancy risk. 1, 2 Even self-limited gross hematuria mandates complete evaluation. 1, 2

For microscopic hematuria, stratify by the following criteria:

High-Risk Features (Mandatory Complete Urologic Evaluation)

• Age ≥60 years (males or females) 2, 4
• Smoking history >30 pack-years 2, 4
• >25 RBCs per high-power field 2
• Any history of gross hematuria 2, 4
• Occupational exposure to benzenes or aromatic amines (dyes, rubber, leather, paint industries) 1, 2, 4
• Irritative voiding symptoms without infection (urgency, frequency, dysuria)—high-risk marker for urothelial malignancy 1, 2
• History of pelvic irradiation 1, 3
• Analgesic abuse 1, 3

Intermediate-Risk Features (Shared Decision-Making for Cystoscopy/Imaging)

• Age 40-59 years (males) or 50-59 years (females) 2
• Smoking history 10-30 pack-years 2
• 11-25 RBCs per high-power field 2

Low-Risk Features (May Defer Imaging, Repeat UA in 6 Months)

• Age <40 years (males) or <50 years (females) 2
• Never smoker or <10 pack-years 2
• 3-10 RBCs per high-power field 2
• No additional risk factors 2

Complete Urologic Evaluation for Non-Glomerular Hematuria

Laboratory Testing

• Serum creatinine and complete metabolic panel to assess renal function 2, 3
• Complete blood count with platelets to evaluate for coagulopathy 2
• Urine culture if infection suspected (obtain before antibiotics) 2, 3
• Voided urine cytology in high-risk patients (age >60, smoking history, irritative symptoms) to detect high-grade urothelial carcinoma and carcinoma in situ 2, 4

Do not obtain urinary cytology or urine-based molecular markers in the initial evaluation of low-risk patients—current guidelines explicitly recommend against this. 1, 2

Imaging: Upper Tract Evaluation

Multiphasic CT urography is the preferred imaging modality for intermediate- and high-risk patients. 2, 3, 4 This includes:

• Unenhanced phase (detects stones)
• Nephrographic phase (detects renal masses)
• Excretory phase (evaluates collecting systems, ureters, bladder)

This protocol comprehensively detects renal cell carcinoma, transitional cell carcinoma, and urolithiasis. 2, 4

Alternatives if CT contraindicated:

• MR urography for patients with contrast allergy or renal insufficiency 2
• Renal ultrasound with retrograde pyelography (less optimal, insufficient for comprehensive evaluation) 2

Traditional intravenous urography (IVU) is acceptable but has limited sensitivity for small renal masses. 2

Cystoscopy: Lower Tract Evaluation

Cystoscopy is mandatory for:

• All patients with gross hematuria 1, 2
• All patients ≥40 years with microscopic hematuria 2, 4
• Intermediate-risk patients through shared decision-making 2

Flexible cystoscopy is preferred over rigid cystoscopy—it causes less pain, has fewer post-procedure symptoms, and demonstrates equivalent or superior diagnostic accuracy. 2

Cystoscopy visualizes bladder mucosa, urethra, and ureteral orifices to detect transitional cell carcinoma (the most frequently diagnosed malignancy in hematuria cases). 2

Critical Clinical Pearls and Pitfalls

Anticoagulation Does Not Explain Hematuria

Pursue full evaluation even if the patient takes antiplatelet or anticoagulant therapy. 1, 2 These medications may unmask underlying pathology but do not cause hematuria themselves. 1, 2 Malignancy risk is similar regardless of anticoagulation status. 2

Benign Prostatic Hyperplasia Does Not Exclude Malignancy

BPH can cause hematuria but does not exclude concurrent bladder or kidney cancer. 2 Gross hematuria attributed to BPH must be proven through appropriate evaluation including cystoscopy and imaging. 2

Persistent Hematuria After Negative Workup Requires Surveillance

If the complete evaluation is negative but hematuria persists:

• Repeat urinalysis at 6,12,24, and 36 months 2, 3
• Monitor blood pressure at each visit 2, 3
• Consider repeat complete evaluation within 3-5 years for persistent hematuria in high-risk patients 2
• After two consecutive negative annual urinalyses, no further testing is necessary 2

Immediate re-evaluation is warranted if:

• Gross hematuria develops 2, 3
• Significant increase in degree of microscopic hematuria 2, 3
• New urologic symptoms appear (flank pain, dysuria, irritative voiding) 2, 3
• Development of hypertension, proteinuria, or evidence of glomerular bleeding 2, 3

Hematuria Can Precede Bladder Cancer by Years

Long-term surveillance is essential in high-risk elderly patients because hematuria can precede bladder cancer diagnosis by many years. 2 Do not discharge patients from follow-up after a single negative evaluation if they have persistent microscopic hematuria and risk factors. 2

Special Considerations for Underlying Conditions

Diabetes and Hypertension

Patients with diabetes or hypertension who develop hematuria require the same systematic evaluation as other patients. 2 However, pay particular attention to:

• Proteinuria assessment: Diabetic nephropathy typically causes proteinuria before hematuria, so isolated hematuria in a diabetic patient should raise suspicion for non-diabetic causes including malignancy 2
• Renal function monitoring: Baseline chronic kidney disease does not preclude urologic evaluation 2
• Medication review: ACE inhibitors, ARBs, and SGLT2 inhibitors do not cause hematuria 2

Kidney Disease

If glomerular indicators are present (dysmorphic RBCs, casts, significant proteinuria, elevated creatinine):

• Refer to nephrology for evaluation of primary renal disease 1, 2, 3
• Complete urologic evaluation may still be necessary if hematuria persists after nephrology assessment, particularly in patients with risk factors for malignancy 2
• Consider additional workup: complement levels (C3, C4), ANA, ANCA, renal ultrasound 2

"Benign familial hematuria" is a misnomer that should be abandoned—it prompts loss to follow-up when annual monitoring is actually indicated. 5 Even isolated microscopic hematuria can progress to chronic kidney disease, particularly with IgA nephropathy, Alport syndrome, or thin basement membrane disease. 5