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Serum Levels of Phosphorus, Parathyroid Hormone, and Calcium and Risks of Death and Cardiovascular Disease in Individuals With Chronic Kidney Disease: A Systematic Review and Meta-analysis

Suetonia C. Palmer, MB ChB, PhD; Andrew Hayen, PhD; Petra Macaskill, PhD; Fabio Pellegrini, MSc; Jonathan C. Craig, MB ChB, PhD; Grahame J. Elder, MB BS, PhD; Giovanni F. M. Strippoli, MD, PhD
JAMA. 2011;305(11):1119-1127. doi:10.1001/jama.2011.308.
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Context Clinical practice guidelines on the management of mineral and bone disorders due to chronic kidney disease recommend specific treatment target levels for serum phosphorus, parathyroid hormone, and calcium.

Objective To assess the quality of evidence for the association between levels of serum phosphorus, parathyroid hormone, and calcium and risks of death, cardiovascular mortality, and nonfatal cardiovascular events in individuals with chronic kidney disease.

Data Sources The databases of MEDLINE (1948 to December 2010) and EMBASE (1947 to December 2010) were searched without language restriction. Hand searches also were conducted of the reference lists of primary studies, review articles, and clinical guidelines along with full-text review of any citation that appeared relevant.

Study Selection Of 8380 citations identified in the original search, 47 cohort studies (N = 327 644 patients) met the inclusion criteria.

Data Extraction The characteristics of study design, participants, exposures, and covariates together with the outcomes of all-cause mortality, cardiovascular mortality, and nonfatal cardiovascular events at different levels of serum phosphorus, parathyroid hormone, and calcium were analyzed within studies. Data were summarized across studies (when possible) using random-effects meta-regression.

Data Synthesis The risk of death increased 18% for every 1-mg/dL increase in serum phosphorus (relative risk [RR], 1.18 [95% confidence interval {CI}, 1.12-1.25]). There was no significant association between all-cause mortality and serum level of parathyroid hormone (RR per 100-pg/mL increase, 1.01 [95% CI, 1.00-1.02]) or serum level of calcium (RR per 1-mg/dL increase, 1.08 [95% CI, 1.00-1.16]). Data for the association between serum level of phosphorus, parathyroid hormone, and calcium and cardiovascular death were each available in only 1 adequately adjusted cohort study. Lack of adjustment for confounding variables was not a major limitation of the available studies.

Conclusions The evidentiary basis for a strong, consistent, and independent association between serum levels of calcium and parathyroid hormone and the risk of death and cardiovascular events in chronic kidney disease is poor. There appears to be an association between higher serum levels of phosphorus and mortality in this population.

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Figure 1. Flow Diagram of the Identification Process for Eligible Studies
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aSummary estimate not possible due to insufficient data.

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Figure 2. Risks of All-Cause Mortality Grouped According to Level of Study Adjustment for Confounding Variables
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The data with dashed lines represent the studies graphically displayed that reported relative risk (RR) per unit change in serum phosphorus, parathyroid hormone, or calcium as continuous and not categorical variables (ie, these studies reported RR × per unit change, and their slope is provided in the graphs). Studies are stratified into adequate adjustment for confounding variables (all 5 covariates: age, race, time receiving dialysis [or estimated glomerular filtration rate], cardiovascular disease, and diabetes mellitus) or partial adjustment (<5 covariates). HD refers to the hemodialysis cohort within the study. PD refers to the peritoneal dialysis cohort within the study.

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Figure 3. Summary Estimates for Risks of All-Cause Mortality and Cardiovascular Mortality Associated With Levels of Serum Phosphorus, Parathyroid Hormone, and Calcium
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Risks of all-cause mortality, cardiovascular mortality, and nonfatal cardiovascular events are shown per 1-mg/dL increase in serum levels of phosphorus, 100-pg/mL increase in serum parathyroid hormone, and 1-mg/dL increase in serum calcium. Summary estimates are not reported when only a single cohort contributed data. CI indicates confidence interval.

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