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...is, inflammation, and calcium deposition (28). Additionally, its primary role may be in bone, where OPG is secreted by osteoblasts to inhibit differentiation and maturation of neighboring osteoclasts =-=(10,29,30)-=-. Higher levels of OPG probably indicate a compensatory increase of OPG locally in the vascular wall to counteract vascular calcium deposition or result from the transition of vascular smooth muscle c...

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...variables or a Pearson’s chisquared test for categorical variables. Multiple imputation by chained equations was used to impute missing covariates (five cycles) before multivariable models were built =-=(25)-=-. The following covariates were imputed using all other covariates as predictors: history of cardiovascular disease (n=2; ,1%), history of diabetes (n=1; ,1%), body mass index (n=33; 5%), index of coe...

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...ct measures of calcification in this study to corroborate this. In fact, the circulating factorsmeasured in this study probably have pleiotropic effects, including roles in apoptosis and inflammation =-=(53)-=-, that could account for the observed associations. Furthermore, we cannot determine whether these factors play a causal role in the development of disease or are markers of the underlying pathophysio...

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...hosphate (11,14). OPG, OPN, and BMP-7 are produced by a variety of cell types, including endothelial and vascular smooth muscle cells, with increased expression in the setting of active calcification =-=(12,14,15)-=-. Numerous clinical studies have demonstrated associations between these biomarkers and measures of vascular calcification and stiffness (16–22). In this study, we evaluated the association between se...

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...hosphate (11,14). OPG, OPN, and BMP-7 are produced by a variety of cell types, including endothelial and vascular smooth muscle cells, with increased expression in the setting of active calcification =-=(12,14,15)-=-. Numerous clinical studies have demonstrated associations between these biomarkers and measures of vascular calcification and stiffness (16–22). In this study, we evaluated the association between se...

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...ves are each associated with higher mortality in patients with ESRD (4). They may be initiated by the uremic milieu, as well as comorbid factors, such as diabetes, inflammation, and hyperphosphatemia =-=(5,6)-=-. Animal models have identified osteoprotegerin (OPG), osteopontin (OPN), bone morphogenic protein-7 (BMP7), and fetuin-A as factors that may regulate calcification in the vasculature (7–13). Fetuin-A...

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... contribute to excess cardiovascular mortality may identify promising therapeutic targets in ESRD. Decades of clinical observations have noted deposition of extraosseous calcium in patients with ESRD =-=(2,3)-=-. Medial calcification of large vessels, intimal calcification of coronary arteries, and calcification of the cardiac valves are each associated with higher mortality in patients with ESRD (4). They m...

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... ESRD (2,3). Medial calcification of large vessels, intimal calcification of coronary arteries, and calcification of the cardiac valves are each associated with higher mortality in patients with ESRD =-=(4)-=-. They may be initiated by the uremic milieu, as well as comorbid factors, such as diabetes, inflammation, and hyperphosphatemia (5,6). Animal models have identified osteoprotegerin (OPG), osteopontin...

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...evelopment of left ventricular hypertrophy (42). Additionally, questions still remain on racial differences in FGF23 and other mineral metabolites, which is beyond the scope of the current manuscript =-=(35)-=-. Although OPG, OPN, and BMP-7 are produced locally in the vascular wall, fetuin-A is produced in the liver. FetuinA concentrations are high in calcified vascular lesions, where it is deposited from t...

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...ves are each associated with higher mortality in patients with ESRD (4). They may be initiated by the uremic milieu, as well as comorbid factors, such as diabetes, inflammation, and hyperphosphatemia =-=(5,6)-=-. Animal models have identified osteoprotegerin (OPG), osteopontin (OPN), bone morphogenic protein-7 (BMP7), and fetuin-A as factors that may regulate calcification in the vasculature (7–13). Fetuin-A...

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...ts (27); however, differences by diabetic status have not been previously reported. OPG is secreted directly from the vascular wall, where it modulates apoptosis, inflammation, and calcium deposition =-=(28)-=-. Additionally, its primary role may be in bone, where OPG is secreted by osteoblasts to inhibit differentiation and maturation of neighboring osteoclasts (10,29,30). Higher levels of OPG probably ind...

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...ication biomarkers may be less informative. Additionally, circulating levels of these biomarkers may be influenced by glucose and insulin levels, which further limits their utility in this population =-=(32,33)-=-. Associations between OPG and mortality among patients without diabetes were independent of inflammation and FGF-23, which is noteworthy because each is an independent risk factor for mortality in pa...

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...g calcification inhibitor, fetuin-A, in patients with calcifying vascular disease. The observed association of higher OPG levels and mortality is consistent with previous reports in dialysis patients =-=(27)-=-; however, differences by diabetic status have not been previously reported. OPG is secreted directly from the vascular wall, where it modulates apoptosis, inflammation, and calcium deposition (28). A...

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...F-23 has been associated with vascular calcification in several studies (37– 39), but not consistently (40), and experimental studies do not support a direct role of FGF-23 in promoting calcification =-=(40,41)-=-. Prior associations between FGF-23 and calcification may be in part due to its correlation with phosphate and klotho deficiency. It is more likely that the role of FGF23 leading to higher mortality i...

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...ication biomarkers may be less informative. Additionally, circulating levels of these biomarkers may be influenced by glucose and insulin levels, which further limits their utility in this population =-=(32,33)-=-. Associations between OPG and mortality among patients without diabetes were independent of inflammation and FGF-23, which is noteworthy because each is an independent risk factor for mortality in pa...

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...s correlation with phosphate and klotho deficiency. It is more likely that the role of FGF23 leading to higher mortality in dialysis patients is due to the development of left ventricular hypertrophy =-=(42)-=-. Additionally, questions still remain on racial differences in FGF23 and other mineral metabolites, which is beyond the scope of the current manuscript (35). Although OPG, OPN, and BMP-7 are produced...

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...ation and is largely attributed to cardiovascular causes. Although survival has improved modestly over the past decade, the annual adjusted mortality rate of 185.8 per 1000 patient-years remains high =-=(1)-=-. Detailed investigations into novel uremia-related risk factors that contribute to excess cardiovascular mortality may identify promising therapeutic targets in ESRD. Decades of clinical observations...

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...ntinuous linear predictor and fetuin-A as a piecewise linear spline. We calculated a C-statistic for each model in the validation cohort and tested for differences in C-statistic across nested models =-=(26)-=-. All analyses were performed using Stata software, special edition 11.0 (Stata Corp., College Station, Texas) and a twosided a value of 0.05. Results The majority of the study population was treated ...

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...rsus normal serum phosphate (.5.5 mg/dl versus #5.5 mg/dl) and the presence of inflammation (defined as serum albumin,3.6 g/dl, C-reactive protein$10 mg/L, or IL-6$3.09 pg/ml, as previously described =-=[24]-=-) using stratified models and interaction terms in model 1. Restricted cubic splines were fit to explore nonlinear relationships between levels of calcification biomarkers and all-cause mortality afte...

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... of Nephrology g/L were associated with increasing mortality, which may account for apparently conflicting results. Alternatively, differences in assay performance may contribute to the heterogeneity =-=(52)-=-. Despite the independent associations that we observed between OPG, fetuin-A, and mortality, the inclusion of these biomarkers did not improve clinical risk prediction in this study, and our findings...

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...is, inflammation, and calcium deposition (28). Additionally, its primary role may be in bone, where OPG is secreted by osteoblasts to inhibit differentiation and maturation of neighboring osteoclasts =-=(10,29,30)-=-. Higher levels of OPG probably indicate a compensatory increase of OPG locally in the vascular wall to counteract vascular calcium deposition or result from the transition of vascular smooth muscle c...

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... contribute to excess cardiovascular mortality may identify promising therapeutic targets in ESRD. Decades of clinical observations have noted deposition of extraosseous calcium in patients with ESRD =-=(2,3)-=-. Medial calcification of large vessels, intimal calcification of coronary arteries, and calcification of the cardiac valves are each associated with higher mortality in patients with ESRD (4). They m...

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...is, inflammation, and calcium deposition (28). Additionally, its primary role may be in bone, where OPG is secreted by osteoblasts to inhibit differentiation and maturation of neighboring osteoclasts =-=(10,29,30)-=-. Higher levels of OPG probably indicate a compensatory increase of OPG locally in the vascular wall to counteract vascular calcium deposition or result from the transition of vascular smooth muscle c...

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...nd fetuin-A as factors that may regulate calcification in the vasculature (7–13). Fetuin-A is secreted by hepatocytes into the circulation, where it forms soluble complexes with calcium and phosphate =-=(11,14)-=-. OPG, OPN, and BMP-7 are produced by a variety of cell types, including endothelial and vascular smooth muscle cells, with increased expression in the setting of active calcification (12,14,15). Nume...

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...nd fetuin-A as factors that may regulate calcification in the vasculature (7–13). Fetuin-A is secreted by hepatocytes into the circulation, where it forms soluble complexes with calcium and phosphate =-=(11,14)-=-. OPG, OPN, and BMP-7 are produced by a variety of cell types, including endothelial and vascular smooth muscle cells, with increased expression in the setting of active calcification (12,14,15). Nume...

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...an Clemente, CA) were measured within 6 months of enrollment. Baseline comorbid conditions were abstracted from predialysis medical records, and the Index of Co-Existent Disease (ICED) was calculated =-=(23)-=-. Deaths were ascertained through March 31, 2009, by linkage with the US Renal Data System. Cause of death was ascertained through December 31, 2004, from the National Death Index, with chart review t...

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...atients without diabetes than among patients with diabetes. Diabetes is a strong independent stimulus for vascular calcification and is associated with poor outcomes among patients receiving dialysis =-=(1,31)-=-. In our study population, cumulative survival was worse among those with than in those without diabetes. It is possible that among a population with a very high prevalence of vascular calcification a...

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... is an independent risk factor for mortality in patients undergoing dialysis (34–36). In fact, FGF-23 has been associated with vascular calcification in several studies (37– 39), but not consistently =-=(40)-=-, and experimental studies do not support a direct role of FGF-23 in promoting calcification (40,41). Prior associations between FGF-23 and calcification may be in part due to its correlation with pho...

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...nd mortality, with loss of statistical significance. Fetuin-A is a negative acute phase reactant that is correlated with other inflammatory markers; therefore, these models may have been overadjusted =-=(46)-=-. It is plausible that inflammation and fetuin-A are factors in a shared pathophysiologic pathway, whereby chronic inflammation contributes to deficiency of fetuinA, promoting dystrophic calcification...

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...c state. Many of the calcification biomarkers, such as OPN, are subject to phosphorylation and other post-translational modifications that affect their biologic activity and that we could not measure =-=(54)-=-, and single measurements may not adequately capture their variability over time. In addition, currently available serum assays do not distinguish between free serum fetuin-A and fetuin-A bound in fet...

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... over time. In addition, currently available serum assays do not distinguish between free serum fetuin-A and fetuin-A bound in fetuin-mineral complexes, which become more prevalent with advancing CKD =-=(55)-=-. Finally, although we found potentially important interactions between the presence of diabetes at baseline and some calcification biomarkers, we did not evaluate the impact of diabetic control on th...