Acute Interstitial Nephritis and Liver Injury After Long-Term Semaglutide Use

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for renal protection in proteinuric kidney disease. Acute kidney injury (AKI) with GLP-1 RAs has been reported as acute tubular injury, acute interstitial nephritis (AIN), or minimal change disease, and is typically temporally associated with GLP-1 RA initiation. Case Description: An 82-year-old female with CKD G3A2, type 2 diabetes, hypertension, and obesity presented with a 10-day history of nausea, vomiting, and anorexia. Long term medications included semaglutide, lisinopril, and allopurinol. Aspirin and atorvastatin were recently initiated for a transient ischemic attack. Laboratory data revealed AKI with creatinine (Cr) of 5.4 mg/dL (baseline 1.4 mg/dL), liver injury, and peripheral eosinophilia. Imaging was unremarkable and extensive infectious and serologic workup was negative. Kidney biopsy revealed severe AIN with numerous eosinophils (Figure). Liver biopsy was also consistent with drug-induced injury. Potential culprit medications including semaglutide were held. Glucocorticoids were initiated and Cr improved to a nadir of 1.4 mg/dL. Given weight gain, poor diabetic control, and prior tolerance, she was rechallenged with semaglutide. Cr subsequently worsened to 1.8 mg/dL and semaglutide was stopped. Prednisone dose was increased, and she was slowly tapered off steroids with Cr remaining stable at 1.6 mg/dL. Tirzepatide was selectively initiated due to continued difficulties with weight and glycemic control, and renal function remained stable. Discussion: While GLP-1 RAs have a good safety profile in clinical trials, isolated reports of AIN and liver injury are reported. Our case is notable for delayed onset of AIN after years of tolerating semaglutide. Additional studies surrounding risks of AKI with different drugs in this class are warranted.Figure - The interstitium shows severe inflammatory infiltrates including lymphocytes, plasma cells, and numerous eosinophils in clusters (up to > 100 eosinophils per HPF). Tubules show focally severe tubulitis.