What are the potential causes of hematuria (blood in urine) and dysuria (painful urination) in a patient without evidence of infection?

Non-Infectious Causes of Hematuria and Dysuria

When hematuria and dysuria occur together without infection, the most critical considerations are urolithiasis (kidney/bladder stones), malignancy (particularly bladder cancer), and interstitial cystitis, with urologic evaluation being mandatory for any patient with gross hematuria or high-risk features. 1

Urologic Causes (Non-Infectious)

Malignancy

• Bladder cancer is the most frequently diagnosed malignancy in hematuria cases and classically presents with painless gross hematuria, though dysuria can occur with irritative tumors 1, 2
• Transitional cell carcinoma accounts for 70-80% of patients experiencing visible hematuria and should be suspected until proven otherwise 2
• Renal cell carcinoma and upper tract urothelial carcinoma can present with hematuria, typically painless 1
• Gross hematuria carries a 30-40% malignancy risk and requires urgent urologic referral even if self-limited 1

Urolithiasis (Kidney/Bladder Stones)

• Symptomatic stone disease classically presents with flank pain or renal colic accompanied by gross hematuria 3
• Urethral stones in male patients can cause both hematuria and dysuria, sometimes requiring ultrasound for identification 4
• Metabolic abnormalities including hypercalciuria and hyperuricosuria can cause microscopic hematuria and predispose to stone formation 1, 5

Benign Prostatic Hyperplasia (BPH)

• BPH is a common benign cause of hematuria in men but does not exclude concurrent malignancy 1, 5
• Gross hematuria attributed to BPH must be proven to be of prostatic etiology through appropriate evaluation 1

Trauma

• Blunt or penetrating trauma to kidneys or lower urinary tract causes hematuria, often with dysuria if urethral injury present 1
• Blood at urethral meatus with pelvic fractures requires retrograde urethrography before catheter placement 1

Glomerular/Renal Parenchymal Causes

Primary Glomerular Diseases

• IgA nephropathy (Berger disease) is a common cause of persistent isolated microscopic hematuria, typically painless 1, 5
• Thin basement membrane nephropathy presents with asymptomatic hematuria and usually follows a benign course 1, 5
• Alport syndrome (hereditary nephritis with hearing loss) causes hematuria without dysuria 1, 5
• Post-infectious glomerulonephritis presents with tea-colored urine, not typically with dysuria 1

Key Distinguishing Features

• Glomerular bleeding is associated with >80% dysmorphic red blood cells on phase contrast microscopy 1, 5
• Presence of red blood cell casts is pathognomonic for glomerular disease 1
• Significant proteinuria (protein-to-creatinine ratio >0.2 g/g) strongly suggests renal parenchymal disease 1
• Tea-colored or cola-colored urine indicates glomerular source rather than urologic 1

Systemic and Other Causes

Medication-Related

• Anticoagulants and antiplatelet agents do not cause hematuria but may unmask underlying pathology requiring investigation 3, 1
• Evaluation should proceed regardless of anticoagulation therapy 3, 1
• Interstitial nephritis from drugs (analgesic nephropathy) can cause hematuria without typical dysuria 1

Metabolic and Vascular

• Hypercalciuria causes microscopic hematuria and may lead to nephrolithiasis with associated dysuria 1, 5
• Nutcracker syndrome (left renal vein compression) causes hematuria with variable proteinuria 1
• Sickle cell disease causes hematuria due to renal papillary necrosis 1

Exercise and Physiologic

• Vigorous exercise causes transient hematuria that resolves with rest, typically without dysuria 1, 5
• Menstrual contamination in women can cause false-positive hematuria 1

Interstitial Cystitis/Bladder Pain Syndrome

• Presents with dysuria, urgency, frequency, and suprapubic pain without infection 1
• May have microscopic hematuria, though not the primary feature 1

Critical Diagnostic Algorithm

Step 1: Confirm True Hematuria

• Verify with microscopic urinalysis showing ≥3 RBCs per high-power field on at least two of three properly collected specimens 3, 1
• Dipstick positivity alone has only 65-99% specificity and requires microscopic confirmation 1, 6

Step 2: Distinguish Glomerular vs. Non-Glomerular Source

• Examine urinary sediment for dysmorphic RBCs (>80% suggests glomerular) and red cell casts 1, 5
• Check for significant proteinuria (spot protein-to-creatinine ratio) 1
• Assess renal function with serum creatinine and BUN 1

Step 3: Risk Stratification for Malignancy

High-risk features requiring complete urologic evaluation: 1, 6

• Age ≥60 years (males) or ≥60 years (females)
• Smoking history >30 pack-years
• Occupational exposure to chemicals/dyes (benzenes, aromatic amines)
• History of gross hematuria
• Irritative voiding symptoms without infection

Step 4: Complete Urologic Evaluation (for non-glomerular hematuria)

• Multiphasic CT urography is the preferred imaging modality for detecting renal cell carcinoma, transitional cell carcinoma, and urolithiasis 1, 6
• Cystoscopy is mandatory for all patients with gross hematuria and high-risk microscopic hematuria to evaluate for bladder cancer 3, 1, 6
• Flexible cystoscopy is preferred over rigid due to less pain and equivalent diagnostic accuracy 1

Step 5: Nephrology Referral Indications

Refer to nephrology if: 1

• Persistent significant proteinuria (protein-to-creatinine ratio >0.2)
• Presence of red cell casts or >80% dysmorphic RBCs
• Elevated creatinine or declining renal function
• Hypertension with hematuria and proteinuria

Common Pitfalls to Avoid

• Never attribute hematuria to anticoagulation alone—these medications unmask underlying pathology that requires investigation 3, 1
• Never ignore gross hematuria, even if self-limited—30-40% malignancy risk mandates urgent urologic referral 3, 1
• Do not obtain urinary cytology or urine-based molecular markers in initial evaluation—not recommended by current guidelines 3
• Do not defer evaluation in patients taking medications like tadalafil (Cialis)—these do not cause hematuria and should not delay workup 1
• Benign causes do not exclude malignancy—even with identified BPH or stones, complete evaluation is required in high-risk patients 1

Age-Specific Considerations

Children

• Glomerulonephritis and congenital anomalies are more common causes 1
• Urethral stones should be considered in boys with hematuria and dysuria 4
• Ultrasound is preferred imaging modality to minimize radiation 1

Adults >35-40 Years

• Malignancy becomes a significant risk factor requiring complete urologic evaluation 3, 1
• Males ≥60 years are classified as high-risk and require cystoscopy and CT urography regardless of other factors 1, 6