Calcium-phosphate levels, linked to vascular dysfunction in chronic kidney disease, may represent novel risk factors for coronary heart disease, stroke, and death in community-dwelling adults.
We tested this hypothesis over 12.6 years of follow-up in the prospective, community-based Atherosclerosis Risk in Communities Study (n = 15,732).
At baseline, mean (SD) values were 9.8 (0.4) mg/dL for serum calcium, 3.4 (0.5) mg/dL for serum phosphate, 33.6 (5.3) mg(2)/dL(2) for calcium-phosphate product, 54.2 (5.7) years for age, and 93.1 (21.5) mL/min per 1.73 m(2) for glomerular filtration rate (GFR). Shared associations of calcium, phosphate, and calcium-phosphate product included older age, female sex, African American race, cigarette-years, current cigarette smoking, low body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, low serum albumin, low GFR, low caloric intake, and phosphorus intake. With adjustment for age, demographic characteristics, comorbid conditions, albumin, and GFR, calcium-associated hazards ratios for coronary heart disease, stroke, and death were, respectively, 1.01 (95% confidence interval 0.96-1.06), 1.16 (1.07-1.26, P = .0005), and 1.03 (0.98-1.08); phosphate-associated hazards ratios were 1.03 (0.98-1.08), 1.11 (1.02-1.21, P = .0219), and 1.14 (1.09-1.20, P < .0001); calcium-phosphate product-associated hazards ratios were 1.03 (0.98-1.08), 1.15 (1.05-1.26, P = .0017), and 1.15 (1.09-1.20, P < .0001).
Although calcium, phosphate, and calcium-phosphate product levels exhibit complex associations with traditional cardiovascular risk factors and outcomes, they may be potentially modifiable risk factors for stroke and death in community-dwelling adults.
"Table 1 summarized the baseline characteristics of included trials. The individuals in studies of Sasiwarang  (2013), Edith  (2013), Matthew  (2010), Ravi D  (2007), Robert N. F  (2008), Bernard M.Y. C  (2009) Tobias E. L  (2010), K. M. Fleming  (2011), Per-Anton Westerberg  (2013), C. J. Bates  (2011), Bernard  (2009) and Julie R. D  (2013) were general population. "
[Show abstract][Hide abstract] ABSTRACT: Background
It is demonstrated that elevated serum levels of alkaline phosphatase (ALP) and phosphate indicate a higher risks of cardiovascular disease (CVD) and total mortality in population with chronic kidney disease (CKD), but it remains unclear whether this association exists in people with normal or preserved renal function.
Clinical trials were searched from Embase and PubMed from inception to 2013 December using the keywords “ALP”, “phosphate”, “CVD”, “mortality” and so on, and finally 24 trials with a total of 147634 patients were included in this study. Dose-response and semi-parametric meta-analyses were performed.
A linear association of serum levels of ALP and phosphate with risks of coronary heart disease (CHD) events, CVD events and deaths was identified. The relative risk(RR)of ALP for CVD deaths was 1.02 (95% confidence interval [CI], 1.01–1.04). The RR of phosphate for CVD deaths and events was 1.05 (95% CI, 1.02–1.09) and 1.04 (95% CI: 1.03–1.06), respectively. A non-linear association of ALP and phosphate with total mortality was identified. Compared with the reference category of ALP and phosphate, the pooled RR of ALP for total mortality was 1.57 (95% CI, 1.27–1.95) for the high ALP group, while the RR of phosphate for total mortality was 1.33 (95% CI, 1.21–1.46) for the high phosphate group. It was observed in subgroup analysis that higher levels of serum ALP and phosphate seemed to indicate a higher mortality rate in diabetic patients and those having previous CVD. The higher total mortality rate was more obvious in the men and Asians with high ALP.
A non-linear relationship exists between serum levels of ALP and phosphate and risk of total mortality. There appears to be a positive association of serum levels of ALP/phosphate with total mortality in people with normal or preserved renal function, while the relationship between ALP and CVD is still ambiguous.
PLoS ONE 07/2014; 9(7):e102276. DOI:10.1371/journal.pone.0102276 · 3.23 Impact Factor
"Risk in Communities Study of communitydwelling adults (n = 15,732), the phosphateassociated , adjusted relative risk of death increased by 14% (p < 0.001) in the highest phosphate tertile . More recently, a reanalysis of the Ramipril in Nondiabetic Renal Failure Study showed that patients with a serum phosphate concentration of 3.5 mg/ dL were more than twice as likely to progress to end-stage renal disease (ESRD) . "
[Show abstract][Hide abstract] ABSTRACT: All-cause mortality and cardiovascular- related mortality have both been linked to abnormal serum phosphate concentrations in chronic kidney disease (CKD). Aberrant serum phosphate concentration in patients with CKD has also been associated with adverse cardiac and renal outcomes. Early prevention or management of rising or high serum phosphate concentrations in patients with CKD is now considered to be an important intervention to prevent downstream complications resulting from the poor management of serum calcium and parathyroid hormone (PTH). It is widely considered that starting phosphate binder therapy early, with concurrent dietary management of serum phosphate, constitutes an effective course of interventions, although normalization of serum phosphate in dialysis patients remains atypical, unless specific dialytic measures are also undertaken. Calcium- based phosphate binders are often the first type of binders prescribed due to their low cost. Evidence shows that most phosphate binders are roughly equally effective in lowering serum phosphate concentrations in adults compared to placebo, with a small probability that sevelamer hydrochloride is better than calcium acetate or lanthanum carbonate. However, not all binders are created equal in regards to their safety profiles. The potential for accumulations and toxicities does exist with very long-term continuous exposure. We discuss these issues in the course of this review.
"In type 2 diabetes, serum phosphate greater than 3.9 mg/dL was associated an increase in cardiovascular mortality . In community dwelling non-CKD, non-CVD adults, higher serum phosphate increased CVD risks after a follow-up period of over 10 years [19,20]. Whether an association between phosphate load and worse outcomes is the result of a direct or indirect effect of phosphate will require further study. "
[Show abstract][Hide abstract] ABSTRACT: Background
Marked hyperphosphatemia, hyperparathyroidism and 25-hydroxyvitamin D deficiency are associated with mortality in dialysis patients. Such data in chronic kidney disease stage 2–4 population are limited. It has been suggested that high-normal serum phosphate predicts worse renal and patient outcomes. The data regarding parathyroid hormone and outcomes in this population is limited. The present study examined mineral metabolism and its association with the development of end-stage renal disease and mortality in stage 2–4 chronic kidney disease patients.
This is a prospective cohort study that included 466 non-dialysis chronic kidney disease stage 2–4 patients. Mineral parameters were obtained at the time of enrollment and the patients were followed prospectively for 25 (1–44) months or until they reached the endpoints of end-stage renal disease or mortality.
Hyperparathyroidism and 25-hydroxyvitamin D deficiency began to occur in the early stages of chronic kidney disease, whereas significant hyperphosphatemia only developed in the later stages. High-normal and mildly elevated serum phosphate (>4.2 mg/dL) predicted the composite outcome of end-stage renal disease or mortality after adjustments for cardiovascular risk factors, chronic kidney disease stage and other mineral parameters. Parathyroid hormone levels above the upper limit of normal (>65 pg/mL) predicted the future development of end-stage renal disease and the composite outcome of end-stage renal disease or mortality after adjustments. 25-hydroxyvitamin D deficiency (<15 ng/mL) was also associated with worse outcomes.
In chronic kidney disease, hyperparathyroidism developed prior to significant hyperphosphatemia confirming the presence phosphate retention early in the course of chronic kidney disease. High-normal serum phosphate and mildly elevated parathyroid hormone levels predicted worse renal and patient outcomes. This data emphasizes the need for early intervention in the care of chronic kidney disease stage 2–4 patients.
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