What is the appropriate evaluation and management for a non-diabetic patient presenting with pyuria (presence of pus in urine) and glucosuria (presence of glucose in urine)?

Evaluation and Management of Non-Diabetic Pyuria and Glucosuria

The combination of pyuria and glucosuria in a non-diabetic patient should prompt immediate evaluation for acute tubulointerstitial nephritis (ATIN), with consideration of HNF1A-MODY and renal tubular disorders as alternative diagnoses.

Immediate Diagnostic Approach

Primary Consideration: Acute Tubulointerstitial Nephritis

Glucosuria (≥1+ on dipstick) in the presence of pyuria has 68% sensitivity and 94% specificity for ATIN in non-diabetic patients with azotemia, with a positive likelihood ratio of 11.24 1. This makes ATIN the most likely diagnosis when both findings coexist.

Key diagnostic steps:

• Assess renal function immediately: Check serum creatinine, BUN, and electrolytes to evaluate for azotemia 1
• Obtain detailed medication history: ATIN is commonly drug-induced (NSAIDs, antibiotics, PPIs) 1
• Evaluate for systemic symptoms: Look for fever, rash, arthralgias, or eosinophilia that suggest drug hypersensitivity 1
• Check urinalysis with microscopy: Confirm pyuria (≥10 WBCs/high-power field) and quantify glucosuria 2
• Assess for other tubular dysfunction markers: Check serum phosphate, uric acid, potassium, and bicarbonate levels 1

Rule Out Urinary Tract Infection First

Before pursuing other diagnoses, exclude symptomatic UTI by assessing for specific urinary symptoms (dysuria, frequency, urgency, fever >38.3°C, gross hematuria) 2.

• If UTI symptoms are present: Obtain urine culture before starting antibiotics, as the combination of positive leukocyte esterase with microscopic WBCs increases diagnostic accuracy substantially 2
• If no UTI symptoms: Do not treat as UTI, as pyuria alone is insufficient for diagnosis and asymptomatic bacteriuria should not be treated 2, 3
• The absence of pyuria effectively rules out UTI with excellent negative predictive value approaching 100% 3, but pyuria presence has low predictive value for actual infection 2

Secondary Diagnostic Considerations

HNF1A-MODY (Maturity-Onset Diabetes of the Young)

HNF1A-MODY presents with lowered renal threshold for glucosuria, progressive insulin secretory defect, and typically manifests in adolescence or early adulthood 4.

Distinguishing features:

• Family history of early-onset diabetes (autosomal dominant inheritance) 4
• Large rise in 2-hour plasma glucose on OGTT (>90 mg/dL or 5 mmol/L) 4
• Sensitivity to sulfonylureas for treatment 4
• Absence of significant renal dysfunction initially 4

Familial Renal Glucosuria (FRG)

FRG is characterized by persistent glucosuria despite normal blood glucose levels and normal tubular function, caused by mutations in the SGLT2 gene 5.

Clinical features to assess:

• Benign, often asymptomatic condition with variable glucose excretion 6, 5
• May present with lower body weight/height, altered blood pressure, or hypercalciuria 5
• Transmitted genetically (autosomal dominant or recessive) 6
• Diagnosis of exclusion after ruling out diabetes and generalized tubular dysfunction 5

Diagnostic Algorithm

Step 1: Confirm Non-Diabetic Status

• Measure fasting plasma glucose and HbA1c to definitively exclude diabetes 4
• HbA1c ≥6.5% (≥48 mmol/mol) is diagnostic of diabetes 4
• Consider OGTT if HNF1A-MODY suspected based on family history and age of presentation 4

Step 2: Assess Renal Function and Tubular Markers

• If serum creatinine elevated (>1.4 mg/dL): ATIN is highly likely with 94% specificity when glucosuria ≥1+ present 1
• Check additional tubular dysfunction markers: Hypophosphatemia, hypouricemia, hypokalemia, and low total CO2 support tubular injury 1
• Quantify proteinuria: Tubular proteinuria (40% in ATIN) versus nephrotic-range proteinuria suggests different pathology 1

Step 3: Determine Need for Kidney Biopsy

Kidney biopsy is indicated when:

• Azotemia persists with unexplained glucosuria and pyuria 1
• Clinical suspicion for ATIN remains high after excluding other causes 1
• Progressive renal dysfunction despite conservative management 7

In ATIN patients undergoing biopsy for azotemia, 1+ or higher glucosuria is a good predictor of diagnosis 1.

Step 4: Consider Genetic Testing

If renal function is normal and ATIN excluded:

• Test for HNF1A mutations if family history of early-onset diabetes and characteristic OGTT pattern 4
• Consider SGLT2 gene testing for FRG if persistent isolated glucosuria without other abnormalities 5

Management Based on Diagnosis

If ATIN Confirmed

• Discontinue offending medication immediately 1
• Monitor renal function closely for recovery 1
• Consider corticosteroids in severe cases with progressive renal dysfunction, though evidence is limited 4

If HNF1A-MODY Diagnosed

• Initiate sulfonylurea therapy as first-line treatment (highly sensitive) 4
• Avoid insulin initially unless absolutely necessary 4
• Provide genetic counseling given autosomal dominant inheritance 4

If FRG Diagnosed

• Reassure patient that condition is generally benign 6, 5
• Monitor for associated features: Blood pressure, bone health (hypercalciuria), growth parameters in children 5
• No specific treatment required in most cases 6

Common Pitfalls to Avoid

• Do not assume all glucosuria in non-diabetics is benign renal glucosuria without excluding ATIN, especially if azotemia present 1
• Do not treat pyuria as UTI without specific urinary symptoms, as this leads to unnecessary antibiotic use and resistance 2, 3
• Do not delay kidney biopsy in patients with unexplained azotemia and glucosuria, as ATIN requires prompt diagnosis and management 1
• Do not overlook medication history, as drug-induced ATIN is common and reversible with early recognition 1
• Do not diagnose diabetes based solely on glucosuria without confirming with plasma glucose or HbA1c testing 4