Kidney biopsy unveiled: multifactorial damage in immune checkpoint inhibitor therapy, a case report

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by enhancing anti-tumor immunity, but may cause immune-related adverse events (IRAEs) in up to 40% of patients. Renal involvement occurs in 1–5% of cases and includes a spectrum of immune-mediated injuries, most commonly acute interstitial nephritis (AIN). We report the case of a 79-year-old man with stage G3A chronic kidney disease and biphasic pleural mesothelioma treated with dual ICI therapy. Eleven days after treatment initiation, he developed acute kidney injury (AKI) and severe hypercalcemia with neurological symptoms. A comprehensive diagnostic work-up excluded the most common causes of hypercalcemia, raising suspicion of an immune-mediated mechanism. Because renal dysfunction persisted despite supportive measures, a kidney biopsy was performed and showed granulomatous AIN with tubular calcium deposition and non-necrotizing epithelioid granulomas, findings consistent, although uncommon, with ICI-related nephrotoxicity. Further imaging findings strongly supported central adrenal insufficiency secondary to hypophysitis as the underlying cause of hypercalcemia. Corticosteroid therapy led to marked clinical improvement, with complete recovery of renal function and resolution of hypercalcemia. This case highlights the diagnostic and prognostic value of kidney biopsy in ICI-associated AKI, as histological findings clarified the interplay between immune-mediated nephrotoxicity, hypercalcemia, and pre-existing CKD, thereby guiding tailored nephrological and oncological management. It also emphasizes that, in patients receiving ICIs, hypercalcemia should raise suspicion for central adrenal insufficiency due to hypophysitis.