Acute Interstitial Nephritis (AIN)
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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Risk factors
- Medications: PPIs (omeprazole, pantoprazole, esomeprazole), NSAIDs, antibiotics (penicillins, cephalosporins, sulfa, rifampin, fluoroquinolones), allopurinol, diuretics, mesalamine
- Checkpoint inhibitors (pembrolizumab, nivolumab, ipilimumab)
- Infections: pyelonephritis, leptospirosis, legionella, CMV, EBV, HIV
- Autoimmune: SLE, Sjögren syndrome, sarcoidosis, IgG4-related disease
- 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
- Pyelonephritis — Flank pain, fever, pyuria, bacteriuria, positive culture
- 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)
Diagnostic algorithm
| Drug Class | Examples | Typical Latency |
|---|---|---|
| Antibiotics | Penicillins, cephalosporins, sulfa, rifampin, fluoroquinolones | 1-3 weeks |
| PPIs | Omeprazole, pantoprazole, esomeprazole | Months |
| NSAIDs | Ibuprofen, naproxen, celecoxib | Weeks-months |
| Diuretics | Furosemide, thiazides | Weeks |
| Antiepileptics | Phenytoin, carbamazepine, lamotrigine | Weeks |
| Others | Allopurinol, mesalamine, immune checkpoint inhibitors | Weeks-months |
Treatment
First-line
- Identify and discontinue offending medication immediately — most important intervention
- Supportive care: volume optimization, electrolyte management, adjust renally cleared medications
- 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
- Praga 2017 — Acute Interstitial Nephritis (Praga and González, NEJM 2017)
- ASN 2022 — American Society of Nephrology Onconephrology guidance on immune checkpoint inhibitor nephrotoxicity
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