SAT-761 - Immune Checkpoint Inhibitor–Induced Calcitriol-Mediated Hypercalcemia in Metastatic Renal Cell Carcinoma

Background
Immune checkpoint inhibitors (ICIs), including Nivolumab and Ipilimumab, are associated with immune-related adverse events (irAEs). Calcitriol-mediated hypercalcemia is a rare endocrine toxicity.

Clinical Case
A 68-year-old man with type 2 diabetes, hypertension, hyperlipidemia, and tobacco use was diagnosed with grade 4 clear cell renal cell carcinoma after presenting with hematuria. He underwent radical nephrectomy with negative margins but later developed biopsy-proven retroperitoneal nodal recurrence and was started on nivolumab plus ipilimumab.
After three cycles, he developed fatigue, anorexia, rash, and severe hypercalcemia (corrected Ca 15.5 mg/dL; ionized Ca 6.0 mg/dL) with suppressed PTH (14.9 pg/mL). Initial management with IV fluids and pamidronate 60 mg resulted in partial improvement without normalization, raising suspicion for a non–PTHrP-mediated mechanism. Further workup showed elevated 1,25-dihydroxyvitamin D (103 pg/mL), low PTH (15.7 pg/mL), 25-OH vitamin D 39 ng/mL, and PTHrP 12 pg/mL, consistent with calcitriol-mediated hypercalcemia.
ICI therapy was held for two months, and prednisone 40 mg daily was initiated with taper, resulting in rapid normalization of calcium and symptom improvement. ICI therapy was later resumed, with sustained normocalcemia off steroids.
His course was complicated by ICI-induced hypothyroidism (TSH 77.9 µIU/mL, undetectable free T4) requiring levothyroxine and steroid-induced hyperglycemia requiring insulin escalation, followed by persistent hyperglycemia after taper, raising concern for evolving ICI-induced autoimmune diabetes; evaluation is ongoing. No hypophysitis has been observed.

Discussion
ICI-associated hypercalcemia due to calcitriol excess is rare and mimics granulomatous disease. Hypercalcemia in this setting is often initially attributed to malignancy, leading to potential delay or misdiagnosis. Recognition is critical, as treatment requires glucocorticoids rather than antiresorptive therapy alone. Concurrent endocrinopathies reflect systemic immune activation.

Conclusion
Calcitriol-mediated hypercalcemia is an uncommon but important ICI-related toxicity. Early identification and corticosteroid therapy are essential and may allow safe continuation of immunotherapy.

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