Malignancy-Associated Hypercalcemia and Kidney Disease: Facts, Controversies, and Management

Hypercalcemia can affect multiple organ systems and, depending on its severity, presents with a wide range of clinical manifestations. Severe hypercalcemia may lead to serious complications such as confusion and encephalopathy. Malignancy-associated hypercalcemia (MAH) occurs in up to 10%-30% of patients with cancer, with a higher incidence in those with advanced disease, and is associated with a poor prognosis. Several mechanisms have been proposed to explain MAH, the most prominent being humoral hypercalcemia of malignancy and osteolytic hypercalcemia. Although less common, recent advances have identified additional mechanisms of MAH, including novel cancer medications such as immune checkpoint inhibitors and prolonged immobilization. While various treatment modalities are available for managing hypercalcemia, dosing of antihypercalcemic medications in patients with kidney dysfunction remains challenging. This comprehensive review illustrates the mechanisms of MAH, discusses relevant investigations, and focuses on management strategies tailored to the severity of hypercalcemia in patients with cancer. Additionally, we address the dose adjustments for antihypercalcemic agents in patients with reduced glomerular filtration rate and explore potential areas for developing targeted therapies to better address MAH.