AIN

**Definition:** Acute interstitial nephritis (AIN, also called tubulointerstitial nephritis) is inflammation and edema of the renal interstitium with a lymphocytic and eosinophilic infiltrate. It causes acute kidney injury (AKI) without primary glomerular or vascular injury.

**Etiologies (high-yield):** - **Drugs (about 70%):** - Beta-lactams (penicillins, methicillin, cephalosporins) - NSAIDs - PPIs - Sulfonamides and sulfa-containing diuretics (furosemide, thiazides) - Rifampin, ciprofloxacin - Allopurinol - Checkpoint inhibitors - Mnemonic: "PPIs, Penicillins, NSAIDs, Sulfa, Rifampin, Allopurinol, Diuretics" - **Infections:** Legionella, Leptospira, CMV, Streptococcus, TB, and others - **Autoimmune/systemic:** SLE, Sjögren syndrome, sarcoidosis, IgG4-related disease, TINU (tubulointerstitial nephritis with uveitis)

**Pathophysiology:** A drug or antigen is processed and presented in the interstitium. This triggers a **type IV (delayed, T-cell-mediated) hypersensitivity** reaction, with some contribution from type I and antibody-mediated mechanisms. The result is interstitial edema, a mononuclear and eosinophilic infiltrate, and tubulitis. Onset is typically **about 7–14 days after exposure** (earlier on re-exposure). It is not dose-dependent. NSAID-induced AIN can take months and often lacks the systemic features.

**Clinical features:** - Classic triad of **fever, rash, and eosinophilia** (present in only about 10–30% of cases) - Arthralgias - AKI with rising creatinine and oliguria or non-oliguria - Possible flank pain - NSAIDs may also cause nephrotic-range proteinuria (concurrent minimal change disease)

**Diagnosis:** - **Urinalysis:** sterile pyuria, **WBC casts**, hematuria, and mild subnephrotic proteinuria. Urine eosinophils (Hansel stain) have poor sensitivity and specificity. - Peripheral eosinophilia (variable) - Fractional excretion of sodium usually >1% (tubular dysfunction) - Possible non-anion-gap metabolic acidosis (renal tubular acidosis) and hyperkalemia from tubular dysfunction - **Renal biopsy (gold standard):** interstitial edema with infiltrate of lymphocytes, plasma cells, and eosinophils, with tubulitis. The glomeruli are generally normal.

**Management:** 1. **Stop the offending drug** (the most important step). 2. Supportive care. 3. **Corticosteroids** if there is no improvement in several days, or if the biopsy shows significant inflammation. 4. Dialysis if indicated. Prognosis is usually good, but delayed recognition can lead to permanent interstitial fibrosis and CKD.

**Differential on boards:** - **ATN (acute tubular necrosis):** muddy brown (granular) casts, FeNa >2%, and ischemic or toxic exposure - **Prerenal AKI:** FeNa <1%, BUN:Cr >20, and hyaline casts - **Glomerulonephritis:** RBC casts, hypertension, and edema - **Chronic analgesic nephropathy:** chronic interstitial nephritis with papillary necrosis, from long-term NSAID or phenacetin use

**Board pearl:** A patient on antibiotics (for example, a beta-lactam) or a PPI who develops AKI with fever, rash, and WBC casts has AIN until proven otherwise.