A 52‑year‑old man with new severe bilateral flank/kidney pain (10/10) worsened by walking, relieved by rest, that began one month after starting hydrochlorothiazide, with a history of back pain, no nausea, vomiting, fever, chills, dysuria, or hematuria, and self‑medicating with IBU (ibuprofen) and APAP (acetaminophen), what is the most likely diagnosis and initial management?

Bilateral Flank Pain After Starting Hydrochlorothiazide: Diagnosis and Management

Most Likely Diagnosis

The most likely diagnosis is hydrochlorothiazide-induced acute interstitial nephritis (AIN), given the temporal relationship (onset 1 month after starting the medication), bilateral flank pain, absence of urinary symptoms, and lack of fever or systemic signs. 1

Immediate Diagnostic Workup

Essential Laboratory Tests

• Obtain urinalysis with microscopy to assess for white blood cells, eosinophiluria, red blood cells, and casts—eosinophiluria strongly suggests drug-induced AIN 1
• Measure serum creatinine and blood urea nitrogen to evaluate for acute kidney injury, as AIN typically develops 5-10 weeks after thiazide initiation with insidious renal function decline 1
• Check complete blood count specifically looking for eosinophilia, which is present in approximately two-thirds of thiazide-induced AIN cases 1
• Assess serum sodium because thiazide-induced hyponatremia can present with nonspecific symptoms including weakness and may develop within 2 weeks of starting therapy 2

Imaging Strategy

• Non-contrast CT abdomen/pelvis is the gold standard first-line imaging study, providing 98-100% sensitivity and specificity for urinary stones while identifying alternative diagnoses in one-third of patients 3, 4
• The bilateral nature of pain and absence of classic renal colic features (colicky, wave-like, position-independent pain radiating to groin) make nephrolithiasis less likely, but imaging is still mandatory to exclude obstruction 3, 4
• If CT shows no stones or hydronephrosis and renal function is declining, the diagnosis of drug-induced AIN becomes highly probable 1

Differential Diagnosis Considerations

Drug-Induced Acute Interstitial Nephritis

• Hydrochlorothiazide causes AIN through a drug-induced hypersensitivity reaction with characteristic findings of interstitial inflammation without immune complex deposition 1
• The 1-month latency period fits the typical 5-10 week window for thiazide-induced AIN 1
• Bilateral flank pain without fever, dysuria, or hematuria distinguishes AIN from pyelonephritis 4

Musculoskeletal Pain

• Pain that improves with rest and worsens with walking suggests a musculoskeletal component, particularly involving paraspinal muscles or facet joints 3, 5
• However, the temporal relationship to medication initiation and bilateral distribution make this a secondary rather than primary diagnosis 3

Nephrolithiasis

• More than 20% of patients with confirmed stones have negative urinalysis for hematuria, so absence of hematuria does not exclude stones 3
• Bilateral stones are uncommon except in patients with metabolic disorders or recurrent stone disease 3
• The pain pattern (improved with rest, worsened by walking rather than colicky and position-independent) is atypical for renal colic 3, 4

Immediate Management Algorithm

Step 1: Discontinue Hydrochlorothiazide Immediately

• Withdrawal of the offending thiazide diuretic leads to remarkable improvement, with renal function returning to normal or near-normal in most cases 1
• Do not wait for confirmatory testing before stopping the medication if clinical suspicion is high 1

Step 2: Blood Pressure Management

• Switch to an alternative antihypertensive class such as ACE inhibitors, ARBs, or calcium channel blockers that do not cause interstitial nephritis 6
• Chlorthalidone should NOT be substituted, as it is also a thiazide-type diuretic with similar nephrotoxic potential 6

Step 3: Renal Function Monitoring

• Repeat serum creatinine within 48-72 hours after drug discontinuation to assess trajectory of kidney injury 1
• If creatinine continues to rise or oliguria develops, consider renal biopsy to confirm AIN and guide potential corticosteroid therapy 1

Step 4: Pain Management

• Continue ibuprofen and acetaminophen for symptomatic relief, but monitor renal function closely as NSAIDs can worsen kidney injury 6
• If pain persists despite drug discontinuation and normal imaging, consider musculoskeletal evaluation with lumbar spine MRI 5

Critical Red Flags Requiring Urgent Intervention

• Development of fever, chills, or systemic symptoms suggests progression to complicated infection (obstructive pyelonephritis) requiring immediate hospitalization 3, 4
• Oliguria or anuria indicates severe AKI potentially requiring dialysis 1, 7
• Hemodynamic instability or shock mandates emergent evaluation 3
• Rapidly rising creatinine despite drug discontinuation may require corticosteroid therapy and nephrology consultation 1

Common Pitfalls to Avoid

• Do not assume all flank pain is kidney-related—the positional nature distinguishes musculoskeletal causes, but medication timing is the key diagnostic clue here 3, 5
• Do not continue thiazide diuretics while "monitoring" the patient—permanent renal damage can occur with continued exposure 1
• Do not substitute one thiazide for another—all thiazide-type diuretics carry similar risk of AIN 6
• Do not delay imaging based on normal urinalysis alone—over 20% of stone patients lack hematuria, and AIN may present with bland urine sediment initially 3, 1
• Do not miss alternative diagnoses on CT—imaging identifies non-urologic pathology in approximately one-third of flank pain cases 3

Follow-Up Strategy

• Recheck creatinine and electrolytes at 1 week, 2 weeks, and 1 month after drug discontinuation to document recovery trajectory 1
• If renal function normalizes, the diagnosis of thiazide-induced AIN is confirmed retrospectively 1
• If pain persists with normal renal function and negative imaging, pursue musculoskeletal evaluation with physical examination for paraspinal tenderness and lumbar spine MRI if indicated 5
• Ensure the patient understands to avoid all thiazide and thiazide-type diuretics permanently 1