Serum Calcium Linked to Long-Term Mortality in Renal Disease
By Laurie Barclay, MD
Medscape Medical News
January 15, 2010 — Serum calcium is linked to long-term mortality in non-dialysis-dependent (NDD) chronic kidney disease (CKD), according to the results of a historic prospective cohort study reported online January 7 in the Clinical Journal of the American Society of Nephrology.
"Elevated serum calcium has been associated with increased mortality in dialysis patients, but it is unclear whether the same is true in [NDD CKD]," write Csaba P. Kovesdy, MD, from Salem Veterans Affairs Medical Center and Salem Research Institute in Virginia, and colleagues. "Outcomes associated with low serum calcium are also not well-characterized."
Using Cox models, the investigators analyzed associations of baseline, time-varying, and time-averaged serum calcium with all-cause mortality in 1243 men with moderate and advanced NDD CKD.
The association of serum calcium with mortality varied on the basis of which statistical models were applied. In models determining long-term average exposure to calcium (baseline fixed-covariate and time-averaged models), higher calcium was associated with increased mortality. For baseline calcium level 1 mg/dL higher, multivariable adjusted hazard ratio was 1.31 (95% confidence interval [CI],1.13 - 1.53; P < .001).
In contrast, in time-varying models determining shorter-term average exposure to calcium by associating the outcome of mortality with the last observed values of the dependent variable (calcium), lower calcium levels were linked to higher death rates.
"Calcium stabilizes the membranes of excitable cells; thus, lower serum calcium can increase neuromuscular excitability, which may explain why lower calcium levels in our time-varying models could have been associated with higher short-term death rates, possibly through a higher incidence of cardiac arrhythmias," the study authors write. "It has been postulated that elevated calcium may play an integral role in engendering cardiovascular calcification in uremic patients. Such a mechanism of action could be a possible explanation for the increased mortality associated with higher time-averaged calcium levels in our study, because it appears more likely that prolonged exposure to higher serum calcium levels would be more likely to promote vascular calcification."
Limitations of this study include retrospective and observational design precluding determination of causality, participants limited to male patients from a single institution, and possible residual confounding. Furthermore, enrolling patients during an extended time period raises the concern that secular trends in medical practices could have affected outcomes based on the time of enrollment.
"Chronic hypercalcemia and acute hypocalcemia are both associated with increased mortality in male patients with moderate and advanced NDD CKD," the study authors conclude. "Thus, maintaining normal serum calcium levels may be beneficial in this patient population, but prospective studies will be needed to determine what the target range for serum calcium should be and how such a target should be achieved to derive the best therapeutic potential. Therapeutic regimens inducing either hypercalcemia or hypocalcemia should be assessed for any potentially deleterious effects in properly designed clinical trials."
This study was supported by an investigator-initiated grant from Genzyme to Dr. Kovesdy (without salary support) and by an National Institute of Diabetes and Digestive and Kidney Diseases grant to Dr. Kovesdy and coauthor Dr. Kalantar-Zadeh. Dr. Kovesdy and Dr. Kalantar-Zadeh have received grant support and/or honoraria from Genzyme, Shire, and Fresenius.
Clin J Am Soc Nephrol. Published online January 7, 2010.