What is the diagnosis and treatment for a patient with hematuria, leukocytes, and ketones in their urine, negative urine culture, and dysuria at the beginning and end of urination?

Diagnosis: Sterile Pyuria with Hematuria – Likely Interstitial Cystitis/Bladder Pain Syndrome

This clinical presentation—hematuria, leukocytes, ketones, negative urine culture, and dysuria at the beginning and end of urination—is most consistent with interstitial cystitis/bladder pain syndrome (IC/BPS), though urologic malignancy must be excluded given the hematuria. 1

Immediate Diagnostic Approach

Confirm true microscopic hematuria by obtaining microscopic urinalysis showing ≥3 RBCs per high-power field on at least two of three properly collected clean-catch midstream specimens, as dipstick alone has limited specificity (65-99%) and can yield false positives. 2, 3

Key Clinical Features to Assess

• Pain characteristics: IC/BPS typically presents with bladder/pelvic pain and pressure/discomfort associated with urinary frequency and strong urge to urinate, with pain at the beginning and end of urination suggesting urethral involvement. 1
• Voiding symptoms: Document number of voids per day, sensation of constant urge to void, and the location, character, and severity of pain. 1
• Risk stratification for malignancy: Age, smoking history (quantified as pack-years), occupational exposure to chemicals/dyes (benzenes, aromatic amines), and any history of gross hematuria are critical risk factors. 2, 4

Laboratory Evaluation

• Serum creatinine to assess renal function and exclude renal parenchymal disease. 1, 3
• Examine urinary sediment for dysmorphic RBCs (>80% suggests glomerular disease) and red cell casts (pathognomonic for glomerular bleeding). 1, 2
• Assess for proteinuria: Significant proteinuria (>500 mg/24 hours or protein-to-creatinine ratio >0.5 g/g) strongly suggests renal parenchymal disease and warrants nephrology referral. 1, 2

Mandatory Urologic Evaluation

Even with suspected IC/BPS, hematuria requires complete urologic evaluation to exclude malignancy. 2, 4

Cystoscopy

• Cystoscopy is mandatory for patients with hematuria and irritative voiding symptoms to exclude bladder cancer and identify Hunner lesions (the only consistent cystoscopic finding diagnostic for IC/BPS). 1, 4
• Flexible cystoscopy is preferred as it causes less pain and has equivalent or superior diagnostic accuracy compared to rigid cystoscopy. 1, 2
• Hunner lesions, if present, confirm IC/BPS and respond well to treatment, making early diagnosis by cystoscopy valuable. 1

Upper Tract Imaging

• Multiphasic CT urography is the preferred imaging modality for intermediate- and high-risk patients to detect renal cell carcinoma, transitional cell carcinoma, and urolithiasis. 1, 2
• Risk stratification: Males ≥40 years, females ≥60 years, smoking history >30 pack-years, or >25 RBCs/HPF are considered high-risk. 2, 4

Differential Diagnosis Considerations

Interstitial Cystitis/Bladder Pain Syndrome

• Clinical diagnosis requires chronic symptoms (≥6 weeks) of bladder/pelvic pain with urinary frequency and urgency, documented negative urine cultures, and exclusion of other confusable disorders. 1
• Ketones in urine may reflect dehydration from fluid restriction (common behavioral adaptation in IC/BPS patients to minimize frequency). 1
• Baseline voiding symptoms and pain levels should be documented using validated tools (GUPI, ICSI, or VAS) to measure treatment response. 1

Eosinophilic Cystitis

• Rare cause of hematuria with dysuria and sterile pyuria, typically presenting with focal bladder wall thickening on imaging. 5
• Diagnosis requires bladder biopsy showing eosinophilic infiltration. 5

Urethral Syndrome

• Dysuria at the beginning and end of urination suggests urethral involvement, which can occur with urethritis, local trauma, or anatomic abnormalities. 6

Treatment Approach for IC/BPS (If Malignancy Excluded)

Initial treatment should be nonsurgical and may include concurrent, multi-modal therapies through shared decision-making. 1

First-Line Therapies

• Behavioral therapies: Timed voiding, urgency suppression, fluid management, and bladder irritant avoidance (caffeine, alcohol). 1
• Pelvic floor physical therapy: Non-invasive therapy provided by trained professionals. 1
• Optimization of comorbidities: Address constipation, genitourinary syndrome of menopause, and other contributing factors. 1

Second-Line Options

• Oral medications: Amitriptyline, pentosan polysulfate (with counseling about potential adverse events), or hydroxyzine. 1
• Intravesical therapies: Dimethyl sulfoxide (DMSO) or lidocaine/heparin combinations. 1

Treatment of Hunner Lesions

• Fulguration or injection of Hunner lesions during cystoscopy, as most patients with these lesions respond well to treatment. 1

Critical Pitfalls to Avoid

• Never attribute hematuria solely to IC/BPS without excluding malignancy, especially in patients with risk factors (age >40 years, smoking history, occupational exposures). 2, 4
• Do not treat sterile pyuria with antibiotics in the absence of true infection, as this leads to antibiotic resistance and delays diagnosis. 1
• Anticoagulation or antiplatelet therapy does not cause hematuria—these medications may unmask underlying pathology, and evaluation should proceed regardless. 2, 3
• Do not defer cystoscopy in patients with persistent hematuria and irritative voiding symptoms, as these are high-risk features for urothelial malignancy. 2, 4

Follow-Up Protocol

If initial urologic evaluation is negative but hematuria persists:

• Repeat urinalysis at 6,12,24, and 36 months with blood pressure monitoring at each visit. 1, 2
• Immediate re-evaluation is warranted if gross hematuria develops, significant increase in microscopic hematuria occurs, or new urologic symptoms appear. 2, 3
• Consider nephrology referral if hematuria persists with development of hypertension, proteinuria, or evidence of glomerular bleeding. 1, 2