What are the causes of sterile pyuria?

Causes of Sterile Pyuria

Sterile pyuria has multiple etiologies that can be broadly categorized into infectious causes with negative standard cultures, inflammatory/autoimmune conditions, structural urologic abnormalities, drug-induced nephritis, and systemic diseases—with the most critical being partially treated UTIs, tuberculosis, sexually transmitted infections, immune checkpoint inhibitor nephritis, interstitial cystitis, and glomerulonephritis. 1

Infectious Causes (Culture-Negative)

• Partially treated urinary tract infections are among the most common causes, occurring when antibiotics are initiated before urine culture collection, resulting in negative bacterial growth despite ongoing inflammation 1

• Tuberculosis of the genitourinary tract requires special culture media and should be suspected in patients with risk factors, chronic symptoms, or sterile pyuria that persists despite standard antibiotic therapy 2, 3

• Sexually transmitted infections, particularly Chlamydia trachomatis and Neisseria gonorrhoeae, cause urethritis with pyuria but negative standard urine cultures 2, 3

• Fastidious organisms including Ureaplasma urealyticum and anaerobic bacteria may not grow on standard culture media 3

Inflammatory and Autoimmune Conditions

• Interstitial cystitis presents with chronic pelvic pain (particularly in women) and sterile pyuria, representing bladder inflammation without infection 1

• Glomerulonephritis of various etiologies causes sterile pyuria, often accompanied by proteinuria, dysmorphic red blood cells, and red cell casts 1

• Systemic lupus erythematosus frequently presents with isolated sterile pyuria, which is associated with active renal disease (75% had active nephritis on biopsy) and non-renal disease activity 4

• Kawasaki disease in children causes sterile pyuria in 30-80% of cases, most commonly in those ≤1 year of age, associated with mononuclear cells (not neutrophils) in urine and more severe inflammatory reactions 5

Drug-Induced Causes

• Immune checkpoint inhibitor therapy can cause nephritis presenting with elevated serum creatinine and sterile pyuria (≥5 WBCs/hpf), requiring prompt recognition and management 1

• Drug-induced interstitial nephritis from various medications including NSAIDs, antibiotics (particularly beta-lactams), and proton pump inhibitors causes sterile pyuria with eosinophiluria in some cases 3

Structural and Urologic Abnormalities

• Urolithiasis causes inflammation without infection, leading to sterile pyuria through mechanical irritation of the urinary tract 1

• Benign prostatic hyperplasia in men can cause sterile pyuria through chronic inflammation and urinary stasis 1

• Urological malignancies including bladder cancer, renal cell carcinoma, and transitional cell carcinoma can present with sterile pyuria 1

• Acute pyelonephritis with insufficient bacterial counts to be detected on standard culture (below typical threshold of 10^5 CFU/mL) can cause sterile pyuria 1

Chronic Kidney Disease

• Chronic kidney disease itself increases the prevalence of asymptomatic sterile pyuria to 30.5% overall (24.1% in non-dialysis CKD and 51.4% in hemodialysis patients), likely due to chronic renal parenchymal inflammation 6

• The majority of urinary WBCs in CKD-associated sterile pyuria are neutrophils, though the percentage is lower compared to infectious pyuria 6

Diagnostic Approach to Sterile Pyuria

• Confirm pyuria with urinalysis showing >5-10 WBCs per high-power field on microscopic examination 1

• Document sterility with urine culture on standard media showing no bacterial growth, ideally collected before any antibiotic administration 1

• Assess for UTI symptoms including dysuria, frequency, urgency, and flank pain to distinguish symptomatic from asymptomatic presentations 1

• Consider special cultures for tuberculosis (acid-fast bacilli culture), sexually transmitted infections (nucleic acid amplification testing for Chlamydia/Gonorrhea), and fastidious organisms when standard cultures are negative 2, 3

• Evaluate medication history specifically for immune checkpoint inhibitors, NSAIDs, antibiotics, and PPIs that can cause interstitial nephritis 1, 3

• Check for proteinuria using spot urine protein-to-creatinine ratio, as significant proteinuria suggests glomerular disease 1

• Obtain imaging with renal ultrasound or CT urography when structural abnormalities, malignancy, or urolithiasis are suspected, particularly in males >35 years with risk factors for urological malignancy 1

Critical Clinical Pitfalls

• Never dismiss sterile pyuria in patients on immune checkpoint inhibitor therapy, as this may represent immune-related nephritis requiring urgent intervention including potential corticosteroid therapy 1

• Always obtain cultures before initiating antibiotics when possible, as partially treated UTIs are a leading cause of sterile pyuria and can confound diagnosis 1

• Consider tuberculosis in high-risk populations (immigrants from endemic areas, immunocompromised patients, those with chronic symptoms) even when standard cultures are negative 2, 3

• Recognize that sterile pyuria in lupus patients indicates active disease, with 75% having active nephritis on biopsy, warranting consideration of increased immunosuppression 4

• In chronic kidney disease patients, sterile pyuria is common (prevalence increases with CKD stage) and may represent chronic inflammation rather than infection, though infectious causes must still be excluded 6