In this episode of Hospital Medicine Unplugged, we unpack acute interstitial nephritis (AIN)—a frequently overlooked cause of acute kidney injury (AKI) driven largely by medications, immune reactions, and systemic diseases. We start with epidemiology clinicians should recognize. AIN accounts for roughly 15–27% of kidney biopsies performed for AKI and about 2.8% of all kidney biopsies overall. Among biopsies done specifically for acute renal failure, AIN represents ~13.5% of cases. Drug-induced AIN dominates the landscape, responsible for 70–90% of biopsy-proven cases, and its incidence appears to be rising—particularly in older adults, where polypharmacy and underutilization of kidney biopsy can obscure the diagnosis. Next we break down the most common causes. • Antibiotics are the leading class, responsible for ~49% of drug-induced AIN, especially penicillins, cephalosporins, rifampin, and fluoroquinolones. • Proton pump inhibitors account for ~14%, with omeprazole the single most common culprit drug. • NSAIDs (~11%) are another major contributor. Other causes include 5-aminosalicylates, diuretics, allopurinol, anticonvulsants, and chemotherapeutic agents. Emerging causes include immune checkpoint inhibitors, reflecting the expanding use of immunotherapy in oncology. We then explore the immunologic pathophysiology. AIN is primarily driven by T-cell–mediated hypersensitivity reactions (Type IV) targeting tubular antigens or drug-related antigens processed by tubular epithelial cells. However, IgE-mediated mast cell activation (Type I hypersensitivity) may also contribute in some cases. The resulting interstitial inflammation and edema can rapidly progress to fibrosis, making early recognition and treatment critical for renal recovery. Histologically, AIN is characterized by interstitial inflammatory infiltrates composed mainly of lymphocytes, macrophages, plasma cells, and sometimes eosinophils, along with tubulitis, interstitial edema, and tubular injury. Glomeruli are typically normal, while interstitial fibrosis and tubular atrophy signal chronicity and worse prognosis. Variants include granulomatous AIN and rare entities like IgM-positive plasma cell tubulointerstitial nephritis. Clinically, the classic triad of fever, rash, and eosinophilia is now uncommon—present in fewer than 10–15% of patients. Instead, most patients present with nonspecific symptoms such as malaise, nausea, or asymptomatic AKI. Non-oliguric AKI is typical, often accompanied by mild proteinuria and tubular dysfunction. Diagnosis relies on clinical suspicion, medication review, and supportive laboratory findings. Urinalysis may show sterile pyuria and white blood cell casts, which are more specific for AIN. Eosinophiluria, historically emphasized, is neither sensitive nor specific. Ultimately, kidney biopsy remains the gold standard when the diagnosis is uncertain. We also review emerging biomarkers that may transform diagnosis. Urinary CXCL9, an interferon-γ–induced chemokine involved in lymphocyte recruitment, has shown excellent diagnostic performance with AUC values up to ~0.94 for AIN detection. Additional candidate biomarkers include urinary TNF-α, IL-9, kidney injury molecule-1 (KIM-1), and soluble C5b-9, reflecting tubular injury and immune activation. Management begins with immediate withdrawal of the offending drug. If kidney function does not improve within 5–7 days, corticosteroid therapy is often initiated, typically prednisone ~40–60 mg daily (~0.8 mg/kg). Evidence suggests that early steroid therapy—within the first 1–2 weeks—improves renal recovery, while prolonged treatment beyond several weeks offers little additional benefit. Finally, we discuss prognosis. About 76% of patients achieve some degree of kidney recovery within six months, with complete recovery in roughly half of steroid-treated cases. However, chronic kidney disease remains common, and long-term studies suggest up to 39% of patients may eventually develop end-stage kidney disease. Poor outcomes are associated with delayed diagnosis, prolonged drug exposure, interstitial fibrosis on biopsy, dialysis requirement, and older age. The key takeaway: acute interstitial nephritis is a common, often medication-related cause of AKI that requires high clinical suspicion, prompt withdrawal of offending drugs, and early consideration of corticosteroids to prevent irreversible kidney damage.
