Hidden Hypercalcemia and Mortality Risk in Incident Hemodialysis Patients

CONTEXT: Neither uncorrected- nor albumin-corrected total calcium reliably predict ionized calcium in patients with end-stage renal disease. However, little is known about the consequences of inaccurate assessment of calcium concentration using total calcium. OBJECTIVE: We hypothesized that hidden hypercalcemia (ie, elevated ionized calcium with normal total calcium) and apparent hypercalcemia (ie, elevated ionized calcium with elevated total calcium) are both associated with increased mortality risk. DESIGN, SETTING, AND PATIENTS: We identified 874 incident hemodialysis patients with measured serum ionized calcium, total calcium, albumin, phosphorus, and bicarbonate from October 2007 to December 2011, using data from a large dialysis organization in the United States. EXPOSURES: Serum concentrations of ionized calcium and total calcium were measured. MAIN OUTCOME MEASURE: The primary outcome was all-cause mortality. RESULTS: There was only fair interindex agreement with calcium status between ionized calcium and uncorrected or corrected total calcium (κ = 0.32 and 0.27, respectively). Among patients with high ionized calcium (>1.32 mmol/liter), 88% and 70% patients were incorrectly categorized as being normocalcemic using uncorrected and corrected total calcium, respectively, and were thus considered to have "hidden hypercalcemia." Compared to patients with low-normal ionized calcium (1.16-1.24 mmol/liter), patients with high ionized calcium had a significantly higher mortality risk (adjusted hazard ratio, 1.77; 95% confidence interval, 1.13-2.75). Furthermore, compared to patients with normocalcemia (ionized calcium 1.16-1.32 mmol/liter), those with hidden hypercalcemia by uncorrected and corrected total calcium also had a higher risk for death (adjusted hazard ratio 1.75 95% confidence interval 1.11-2.75 and 1.80 95% confidence interval, 1.11-2.90, respectively). CONCLUSION: The majority of end-stage renal disease patients with elevated ionized calcium are incorrectly categorized as normocalcemic using conventional total calcium measurements; these patients have a higher death risk. Future research is needed to establish whether reducing ionized calcium concentrations in these patients improves clinical outcomes.