Drug-induced or immune-mediated tubulointerstitial inflammation causing AKI.
Also known as: AIN, acute interstitial nephritis, drug-induced interstitial nephritis
Overview
An acute kidney injury characterized by inflammatory infiltrate of the renal interstitium with relative sparing of glomeruli and vessels. Most commonly drug-induced (>70%); also caused by infections, autoimmune disease, and idiopathic processes.
Epidemiology
Underdiagnosed cause of AKI; biopsy series suggest 5-15% of unexplained AKI is AIN. Incidence rising with proton pump inhibitor and checkpoint inhibitor use.
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Question 1RenalMedium
A 52-year-old woman starts trimethoprim-sulfamethoxazole and develops fever, rash, eosinophilia, and acute kidney injury. Urinalysis shows WBC casts. Which of the following is the most appropriate initial management?
AStart high-dose loop diuretics
BBegin maintenance hemodialysis
CStop the offending medication
DGive broad empiric antibiotics
Reveal answer & full explanation
Correct answer: C — Stop the offending medication
AStart high-dose loop diuretics
BBegin maintenance hemodialysis
CStop the offending medication✓
DGive broad empiric antibiotics
Why Stop the offending medication is correct
The fever-rash-eosinophilia-AKI cluster with WBC casts is acute interstitial nephritis from a hypersensitivity reaction.
Removing the trigger is the essential first step and often allows renal recovery on its own.
Corticosteroids are added only if function fails to improve after withdrawal.
Why the others are wrong
Start high-dose loop diuretics — Diuretics treat volume overload, not immune tubular injury, and do nothing for the mechanism; a creatinine-management trap.
Begin maintenance hemodialysis — Dialysis is reserved for refractory or life-threatening AKI, not the initial step in reversible AIN.
Give broad empiric antibiotics — More antibiotics could worsen the drug reaction; WBC casts here reflect inflammation, not pyelonephritis.
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Tubulointerstitial nephritis and uveitis (TINU) syndrome
Pathophysiology
Most drug-induced AIN is a delayed (type IV) hypersensitivity reaction independent of dose. Drug or drug-protein complexes act as haptens, triggering T-cell-mediated interstitial inflammation, eosinophil and lymphocyte infiltration, and tubular injury. Persistent inflammation leads to interstitial fibrosis if not addressed.
Clinical presentation
Symptoms
Often nonspecific: malaise, nausea, anorexia
Classic triad (fever, rash, eosinophilia) present in <10% — historically associated with methicillin
Flank pain in some cases
Many patients asymptomatic with AKI discovered on routine labs
Symptoms develop typically 1-3 weeks after starting offending drug (longer for NSAIDs and PPIs — months)
Signs / physical exam
Maculopapular rash (~15%)
Low-grade fever
Mild hypertension
Often unremarkable physical exam
Classic findings
Recent antibiotic exposure + AKI + sterile pyuria with eosinophils and WBC casts.
Differential diagnosis
Acute tubular necrosis — Recent ischemic or toxic insult; muddy brown casts; no eosinophils; no systemic hypersensitivity features
Prerenal AKI — Volume depletion; FENa <1%; bland sediment; responds to volume
Glomerulonephritis — Dysmorphic RBCs, RBC casts, heavy proteinuria, hypertension
Atheroembolic disease — Post-procedural; livedo reticularis, blue toes, eosinophilia
Diagnostic workup
Diagnostic criteria
Clinical diagnosis suggested by AKI + recent drug exposure + supportive sediment. Kidney biopsy is gold standard, showing interstitial inflammatory infiltrate (lymphocytes, eosinophils, plasma cells) with tubulitis. Biopsy recommended when diagnosis uncertain or no improvement after drug withdrawal.
Labs
BMP — AKI with elevated creatinine
Urinalysis with microscopy — sterile pyuria, WBC casts, eosinophiluria (Hansel or Wright stain — low sensitivity ~30%)
Mild proteinuria (subnephrotic, except NSAID-induced AIN which can cause nephrotic-range)
CBC with differential — peripheral eosinophilia (~30-50%, more common in antibiotic AIN)
Drug review with detailed exposure history including OTC and herbal
Imaging
Renal ultrasound — normal-sized kidneys, no obstruction; sometimes increased echogenicity
Gallium scan — historically used but rarely now (poor specificity)
Monitor creatinine — often improves within days to weeks after drug withdrawal
Treat any underlying infection
If multiple potential drugs, stop all non-essential agents
Second-line / adjunct
Glucocorticoids — prednisone 0.5-1 mg/kg/day for 4-6 weeks with taper — for biopsy-proven AIN with persistent AKI after drug withdrawal (typically started within 1-2 weeks)
Pulse methylprednisolone (250-500 mg × 3 days) for severe AKI requiring dialysis
Mycophenolate mofetil — second-line for steroid-refractory or steroid-dependent cases
Checkpoint inhibitor-induced AIN: hold ICI, give high-dose steroids, restart cautiously per oncology
Avoid re-exposure to the offending drug — note as allergy/adverse reaction
Complications
Incomplete recovery with residual CKD (40-60% have permanent reduction in GFR)
Progression to ESRD if delayed treatment or chronic NSAID/PPI exposure
Interstitial fibrosis from delayed diagnosis
Steroid-related complications
Re-exposure can cause rapid recurrence
PANCE pearls
Classic triad of fever, rash, eosinophilia is present in <10% of patients — its absence does NOT exclude AIN.
PPIs and NSAIDs cause AIN over weeks to months (vs antibiotics over 1-3 weeks). Always review the full medication list.
Eosinophiluria has low sensitivity (~30%) and specificity (also positive in atheroemboli, UTI, prostatitis). Negative test does not exclude AIN.
Biopsy is recommended if creatinine does not improve within 1-2 weeks of stopping the suspected drug, before committing to steroids.
NSAID-induced AIN can present with nephrotic-range proteinuria (concurrent minimal change-like glomerular involvement).
References
KDIGO 2012 — KDIGO Clinical Practice Guideline for Acute Kidney Injury
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