What is the significance and recommended work‑up for a urine sample that shows leukocytes and red blood cells?

Evaluation and Management of Leukocytes and RBCs in Urine

The presence of both leukocytes and red blood cells in urine requires confirmation with microscopic urinalysis showing ≥3 RBCs per high-power field and assessment for urinary tract infection, followed by risk-stratified evaluation for urologic malignancy or glomerular disease depending on clinical context. 1, 2

Initial Confirmation and Triage

Confirm true hematuria with microscopic examination showing ≥3 RBCs/HPF on at least two of three properly collected clean-catch midstream specimens before initiating extensive work-up, as dipstick testing has only 65-99% specificity and can yield false positives. 1, 2 The combination of leukocytes and RBCs does not automatically indicate infection—this pattern can represent UTI, urologic malignancy, glomerulonephritis, or urolithiasis. 1, 2

Obtain urine culture before starting antibiotics if infection is suspected, as pyuria does not exclude concurrent malignancy and infection may mask cancer. 1 The sensitivity of leukocyte esterase is 83% and specificity 78%, while nitrite sensitivity is only 53% (though specificity is 98%), making culture essential for definitive diagnosis. 3, 4

Distinguish Infection from Other Causes

If UTI is Confirmed (positive culture with symptoms):

• Treat the infection appropriately and repeat urinalysis 6 weeks after completing antibiotics. 1, 2
• If hematuria resolves after treatment in a low-risk patient, no further urologic work-up is required. 1
• If hematuria persists after infection treatment, proceed immediately with complete urologic evaluation regardless of age or risk factors, as persistent hematuria after appropriate antibiotic therapy strongly suggests non-infectious etiology such as malignancy. 1

If No Infection (negative culture, asymptomatic bacteriuria, or sterile pyuria):

Do not prescribe antibiotics for asymptomatic pyuria with hematuria—this leads to antibiotic resistance, Clostridioides difficile infection, and delays cancer diagnosis. 1 Hematuria requires evaluation for urologic causes including malignancy, stones, and glomerular disease, not antibiotic treatment. 1

Risk Stratification for Urologic Malignancy

Any episode of gross (visible) hematuria warrants urgent urologic evaluation with cystoscopy and upper tract imaging, given the 30-40% risk of malignancy, regardless of whether bleeding is self-limited or infection is present. 1, 2

High-Risk Features Requiring Full Urologic Evaluation:

• Age ≥40 years (some guidelines use ≥35 or ≥60 years) 5, 1, 2
• Smoking history >30 pack-years 1, 2
• History of gross hematuria 1, 2
• Occupational exposure to chemicals/dyes (benzenes, aromatic amines) 5, 1, 2
• Irritative voiding symptoms without documented infection 5, 1, 2
• Degree of hematuria >25 RBCs/HPF 1

Patients with any high-risk feature require multiphasic CT urography and cystoscopy even if UTI is present or treated. 1, 2

Evaluate for Glomerular Disease

Examine urinary sediment for dysmorphic RBCs (>80% suggests glomerular origin) and red cell casts (pathognomonic for glomerular disease). 5, 1, 2 The presence of tea-colored or cola-colored urine, significant proteinuria, or dysmorphic RBCs indicates glomerular disease and requires nephrology referral in addition to completing urologic evaluation. 1, 2

Nephrology Referral Indicated When:

• Protein-to-creatinine ratio >0.5 g/g (or >500 mg/24 hours) 5, 2
• Dysmorphic RBCs >80% or red cell casts present 5, 1, 2
• Elevated serum creatinine or declining renal function 5, 2
• Hypertension accompanying hematuria and proteinuria 5, 2

The presence of glomerular features does not eliminate the need for urologic evaluation—malignancy can coexist with medical renal disease, so both evaluations should be completed. 1

Complete Urologic Evaluation (When Indicated)

Upper Tract Imaging:

Multiphasic CT urography is the preferred imaging modality, including unenhanced, nephrographic, and excretory phases to detect renal cell carcinoma, transitional cell carcinoma, and urolithiasis. 5, 1, 2 Renal ultrasound alone is insufficient for comprehensive upper tract evaluation. 1

Lower Tract Evaluation:

Flexible cystoscopy is mandatory for all patients ≥35-40 years with microscopic hematuria and any high-risk features, as it provides direct visualization of bladder mucosa, urethra, and ureteral orifices with less pain and equivalent or superior diagnostic accuracy compared to rigid cystoscopy. 5, 1, 2

Urine cytology should be obtained in high-risk patients (age >60 years, smoking >30 pack-years, occupational exposures) to detect high-grade urothelial carcinomas and carcinoma in situ. 1, 2

Follow-Up Protocol

If initial work-up is negative but hematuria persists, repeat urinalysis at 6,12,24, and 36 months with blood pressure monitoring at each visit. 5, 1, 2 After two consecutive negative annual urinalyses, further testing is unnecessary. 1

Immediate re-evaluation is warranted if:

• Gross hematuria develops 5, 1, 2
• Significant increase in microscopic hematuria 5, 1, 2
• New urologic symptoms appear 5, 1, 2
• Development of hypertension, proteinuria, or evidence of glomerular bleeding 5, 1, 2

Critical Pitfalls to Avoid

Never attribute hematuria solely to anticoagulation or antiplatelet therapy—these medications may unmask underlying pathology but do not cause hematuria, and evaluation must proceed regardless. 1, 2 Never ignore gross hematuria, even if self-limited, due to the 30-40% malignancy risk. 1, 2 Do not delay cancer evaluation by prescribing multiple courses of antibiotics for persistent hematuria—this provides false reassurance and worsens outcomes, as diagnostic delays beyond 9 months are associated with worse cancer-specific survival. 1