Mineral Abnormalities in Dialysis Patients May Up Mortality

Pam Harrison

January 27, 2015

High levels of both serum calcium and serum phosphorus in patients receiving any form of dialysis are associated with an increased risk for all-cause and cause-specific mortality, according to a large, nationally representative cohort of patients receiving dialysis.

The study was published online January 22 in the Journal of the American Society of Nephrology.

Matthew Rivara, MD, from the University of Washington, Seattle, and colleagues found that after adjustment for serum albumin concentrations, a calcium concentration 10.2 mg/dL or higher was associated with a 65% greater risk for all-cause mortality (hazard ratio, 1.65; 95% confidence interval [CI], 1.42 - 1.91) in patients receiving peritoneal dialysis and a 59% greater risk for all-cause mortality (HR, 1.59; 95% CI, 1.53 - 1.65) in patients receiving hemodialysis compared with reference serum calcium levels of 9.0 to lower than 9.5 mg/dL.

Serum phosphorus levels of 6.4 mg/dL or higher were also associated with an increased risk for all-cause and cause-specific mortality, irrespective of dialysis modality.

"These results are of particular importance given the selection of uncorrected calcium >10.2 mg/dL as the serum calcium threshold for the first Medicare [end-stage renal disease] clinical mineral metabolism, [Quality Incentive Program] measure," the authors write. "Future studies should investigate whether aggressive control of hypercalcemia and hyperphosphatemia in patients undergoing dialysis results in improved clinical outcomes."

Investigators obtained data on 129,076 patients receiving dialysis, the majority of whom were receiving hemodialysis, treated in DaVita, Inc, facilities between July 2001 and June 2006.

In unadjusted analysis, the highest risk for death was observed among patients receiving either dialysis modality who had unadjusted serum calcium concentrations lower than 8.5 mg/dL, as well as among patients receiving hemodialysis who had unadjusted calcium concentrations of 10.2 mg/dL or higher.

However, serum albumin levels "markedly" confounded associations of uncorrected serum calcium with both all-cause and cause-specific mortality, as the authors point out, especially for the association of low serum calcium with each mortality outcome in both dialysis groups.

"In contrast, albumin adjustment substantially strengthened associations of high serum calcium concentrations with each mortality outcome," they add.

As the authors note, the profound influence of serum albumin as a confounder in the relationship between uncorrected serum calcium and mortality was "not surprising," given that almost one half of circulating calcium is bound to albumin and patients with the lowest total uncorrected serum calcium concentrations also have the lowest serum albumin levels.

Serum albumin has also long been recognized as a robust predictor of mortality in patients receiving dialysis such that the increased mortality risk seen in patients with lower serum calcium levels was likely confounded by the association between low serum albumin and increased mortality risk.

On adjustment for demographic characteristics plus serum albumin, a serum phosphorus level of 6.4 mg/dL or higher was associated with a 48% increased risk for all-cause and cause-specific mortality (HR, 1.48; 95 CI, 1.34 - 1.63) for patients receiving peritoneal dialysis and a 50% greater risk for all-cause and cause-specific mortality (HR, 1.50; 95% CI, 1.47 - 1.54) for patents receiving hemodialysis.

As the authors point out, only 5% of patients in the entire study group had serum calcium concentrations of 10.2 mg/dL or higher.

"In most cases, high serum calcium in patients with [end-stage renal disease] is iatrogenic from the use of vitamin D receptor-activating medications and calcium-containing phosphate binders," they write. "Thus, identification of patients on dialysis with extreme values of serum calcium may be useful in triggering important clinical interventions."

Confirmation of Previous Studies

Asked to comment on the study, Jeffrey Berns, MD, from the Hospital of the University of Pennsylvania, Philadelphia, told Medscape Medical News that the study confirms what was previously known about the association between low and moderately high serum calcium, as these levels were associated with poorer outcomes.

It also confirms the associations between hyperphosphatemia and poorer outcomes, which have been reported before.

"To me, the primarily novel part of this study [was] the focus on the 10.2 mg/dL as a breakpoint for increased mortality risk, especially since that breakpoint has been recommended as a quality metric," Dr Berns said.

The reason why the 10.2 mg/dL or greater breakpoint was proposed as a quality metric in the first place was that at 10.2 mg/dL or greater, level of serum calcium might be a potential marker of drug overuse of calcium-containing phosphate binders or active vitamin D analogs.

"Many people, including myself, feel that at least excessive use of calcium-containing phosphate binders is probably not a good thing," Dr Berns said. "But like many other areas in nephrology, we know that there is an association between calcium-containing phosphate binders and poorer outcomes, but there is no good evidence to suggest that avoidance of calcium-containing phosphate binders improves important outcomes."

Similarly, the suggestion that patients receiving dialysis with both low and, more important, moderately high serum calcium levels of 10.2 mg/dL or higher have poorer outcomes corroborates previous observations. "[B]ut again, whether this is due to excessive use of active vitamin D or excessive use of calcium-containing phosphate binders or too high a dialysate calcium or hyperparathyroidism, we don't know," Dr Berns said.

The study was supported by the National Institutes of Health and the National Institute of Diabetes and Digest and Kidney Diseases. Two coauthors received research grants from DaVita, Inc, one of whom also has received research grants, served as ad hoc consultant, and received honoraria from Baxter Health Care. One coauthor is an employee of DaVita, Inc. The other authors and Dr Berns have disclosed no relevant financial relationships.

J Am Soc Nephrol. Published online January 22, 2015. Full text

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