Utility of N-terminal Parathyroid Hormone-Related Protein in Evaluating Hypercalcemia in Patients with CKD

Introduction: Humoral hypercalcemia of malignancy (HHM) is commonly seen among patients with cancer, and its incidental finding in asymptomatic individuals may be the first indication of an occult malignancy. Parathyroid hormone-related protein (PTH-RP) has been implicated as the circulating factor mediating HHM. However, the diagnostic evaluation of HHM in the setting of CKD can be challenging due to associated alterations in parathyroid (PTH) physiology as well as impaired clearance of PTH-RP metabolites among these patients. Case Description: A 48-year old female, with CKD 5 from Diabetic Kidney Disease on hemodialysis since 2018, consulted for incidental finding of hypercalcemia. 8 months prior, she was diagnosed with secondary hyperparathyroidism given her hyperphosphatemia, hypocalcemia, and elevated PTH levels. Interim, she was prescribed dietary modifications and non-calcium-based phosphate binders. However, on her most recent laboratory tests, she was noted to have mild hypercalcemia, normophosphatemia, normal vitamin D3 levels, and low-normal PTH levels. She was asymptomatic and denied intake of calcium or vitamin D supplements. Rest of the ancillary history was non-contributory. Her vital signs were normal, and systemic physical exam was unremarkable. Since a PTH-independent cause was considered, N-terminal PTH-RP assay was requested, which came out elevated thus confirming the suspicion of HHM. Screening mammogram revealed an irregularly-shaped, high-density right breast mass. Core needle biopsy and immunohistochemistry staining showed invasive ductal carcinoma (pT2N1M0; grade I; positive for estrogen and progesterone receptors; negative human epidermal receptor-2 status). She was then scheduled for lumpectomy, and adjuvant hormonal therapy. Post-operatively, her calcium levels gradually normalized. Discussion: Historical trends of calcium, phosphate, and vitamin D levels can aid clinicians to identify concomitant PTH-independent hypercalcemia among patients with CKD. When an occult malignancy is suspected, clinicians should specifically request for N-terminal PTH-RP assays to accurately confirm the diagnosis of HHM. Although more commonly available, C-terminal PTH-RP levels can be falsely elevated in patients with CKD without cancer due to reduced glomerular filtration in this population.