Related Experiment Video
Updated: Mar 23, 2026
A Semi-Automated and Reproducible Biological-Based Method to Quantify Calcium Deposition In Vitro
Published on: June 2, 2022
Hidden Hypercalcemia and Mortality Risk in Incident Hemodialysis Patients
Yoshitsugu Obi1, Rajnish Mehrotra1, Matthew B Rivara1
1Division of Nephrology and Hypertension (Y.O., E.S., C.M.R., W.L.L., K.K.-Z.), Harold Simmons Center for Kidney Disease Research and Epidemiology, University of California Irvine, School of Medicine, Orange, California 92868; Division of Nephrology (R.M., M.B.R.), Kidney Research Institute and Harborview Medical Center, University of Washington, Seattle, Washington 98104; Division of Nephrology (C.P.K.), University of Tennessee Health Science Center, Memphis, Tennessee 38103; Nephrology Section (C.P.K.), Memphis VA Medical Center, Memphis, Tennessee 38104; Fielding School of Public Health at University of California at Los Angeles (K.K.-Z.), Los Angeles, California 90024; and Los Angeles Biomedical Research Institute at Harbor-University of California at Los Angeles (K.K.-Z.), Torrance, California 90502.
Insights
Total calcium measurements often misclassify ionized calcium levels in end-stage renal disease patients, leading to "hidden hypercalcemia" and increased mortality risk. Accurate ionized calcium assessment is crucial for better patient outcomes.
Area of Science:
- Nephrology
- Clinical Chemistry
- Biomedical Science
Background:
- Total calcium measurements, even when corrected for albumin, are unreliable for assessing ionized calcium in end-stage renal disease (ESRD) patients.
- Inaccurate calcium assessment may have significant clinical consequences, particularly regarding mortality risk.
Purpose of the Study:
- To investigate the association between misclassified calcium status (hidden or apparent hypercalcemia) and all-cause mortality in hemodialysis patients.
- To evaluate the reliability of uncorrected and albumin-corrected total calcium in predicting ionized calcium levels.
Main Methods:
- Retrospective analysis of 874 incident hemodialysis patients with measured serum ionized calcium, total calcium, albumin, phosphorus, and bicarbonate.
- Comparison of calcium status determined by ionized calcium versus total calcium measurements.
- Survival analysis to assess mortality risk associated with different calcium categories.
Main Results:
- Fair agreement was observed between ionized calcium and total calcium measurements (κ = 0.32–0.27).
- A significant proportion of patients with high ionized calcium were misclassified as normocalcemic using total calcium, termed "hidden hypercalcemia".
- High ionized calcium and "hidden hypercalcemia" were significantly associated with increased all-cause mortality risk.
Conclusions:
- Conventional total calcium measurements frequently misclassify ionized calcium levels in ESRD patients, leading to underdiagnosis of hypercalcemia.
- Patients with "hidden hypercalcemia" face a higher risk of death, underscoring the need for accurate ionized calcium monitoring.
- Further research is warranted to determine if interventions targeting ionized calcium levels can improve outcomes in ESRD 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.
Related Concept Videos
01:24Hemodialysis II: Procedure and Complications
01:24Chronic Kidney Disease II: Clinical Manifestations
01:25Hemodialysis III: Nursing Management
01:21Skeleton and Calcium Homeostasis
01:25Peritoneal Dialysis III: Nursing Management
01:25Peritoneal Dialysis II: Peritoneal Dialysis Systems and Complications