Relationship of serum fibroblast growth factor 23 with cardiovascular disease in older community-dwelling women

in European Journal of Endocrinology
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  • 1 Department of Ophthalmology, Division of Endocrinology, Longitudinal Studies Section, Mailman School of Public Health, Johns Hopkins University School of Medicine, M015, Smith Building, 400 North Broadway, Baltimore, Maryland 21287, USA

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Objective

Although fibroblast growth factor 23 (FGF23) has been implicated in the pathogenesis of cardiovascular disease, the relationship between FGF23 and cardiovascular disease has not been well characterized in the general population. The aim of this study was to determine whether serum FGF23 is independently associated with cardiovascular disease in older community-dwelling women.

Design and methods

A cross-sectional design was used to examine the relationship between serum FGF23 and cardiovascular disease. The subjects consisted of a population-based sample of 659 women, aged 70–79 years, who participated in the Women's Health and Aging Studies in Baltimore, Maryland. Prevalent cardiovascular disease (coronary heart disease, stroke, congestive heart failure, and peripheral artery disease) was assessed through diagnostic algorithms and physician adjudication.

Results

Of the 659 women, 185 (28.1%) had cardiovascular disease. Median (25th, 75th percentile) intact serum FGF23 was 34.6 (25.2, 46.2) pg/ml. The prevalence of cardiovascular disease in the lowest, middle, and highest tertile of serum FGF23 was 22.6, 24.9, and 36.7% respectively (P=0.002). Serum log FGF23 was associated with cardiovascular disease (odds ratio per 1 s.d. increase=1.23, 95% confidence interval 1.17, 1.30; P<0.0001) in a multivariable logistic regression model, adjusting for age, race, smoking, education, body mass index, cognition, diabetes, hypertension, physical activity, total cholesterol, high-density lipoprotein cholesterol, and renal function.

Conclusion

Elevated serum FGF23 concentrations are independently associated with prevalent cardiovascular disease in older community-dwelling women. Further studies are needed to elucidate the potential biological mechanisms by which FGF23 may be involved in the pathogenesis of cardiovascular disease.

Abstract

Objective

Although fibroblast growth factor 23 (FGF23) has been implicated in the pathogenesis of cardiovascular disease, the relationship between FGF23 and cardiovascular disease has not been well characterized in the general population. The aim of this study was to determine whether serum FGF23 is independently associated with cardiovascular disease in older community-dwelling women.

Design and methods

A cross-sectional design was used to examine the relationship between serum FGF23 and cardiovascular disease. The subjects consisted of a population-based sample of 659 women, aged 70–79 years, who participated in the Women's Health and Aging Studies in Baltimore, Maryland. Prevalent cardiovascular disease (coronary heart disease, stroke, congestive heart failure, and peripheral artery disease) was assessed through diagnostic algorithms and physician adjudication.

Results

Of the 659 women, 185 (28.1%) had cardiovascular disease. Median (25th, 75th percentile) intact serum FGF23 was 34.6 (25.2, 46.2) pg/ml. The prevalence of cardiovascular disease in the lowest, middle, and highest tertile of serum FGF23 was 22.6, 24.9, and 36.7% respectively (P=0.002). Serum log FGF23 was associated with cardiovascular disease (odds ratio per 1 s.d. increase=1.23, 95% confidence interval 1.17, 1.30; P<0.0001) in a multivariable logistic regression model, adjusting for age, race, smoking, education, body mass index, cognition, diabetes, hypertension, physical activity, total cholesterol, high-density lipoprotein cholesterol, and renal function.

Conclusion

Elevated serum FGF23 concentrations are independently associated with prevalent cardiovascular disease in older community-dwelling women. Further studies are needed to elucidate the potential biological mechanisms by which FGF23 may be involved in the pathogenesis of cardiovascular disease.

Introduction

Abnormalities in phosphate and calcium metabolism have recently been implicated as risk factors for cardiovascular disease and all-cause mortality, particularly in patients with chronic kidney disease (1, 2, 3). Fibroblast growth factor 23 (FGF23) is a recently discovered 30 kDa secreted hormone glycoprotein that plays an important role in the complex and tightly regulated mechanism of mineral metabolism (4). In healthy individuals, FGF23 is secreted from bone osteocytes in response to an increase in dietary phosphate (5). FGF23 acts through one of the FGF-receptors, with klotho as a co-receptor, to inhibit renal phosphate reabsorption and decrease circulating levels of 1,25(OH)2D, and possibly inhibit PTH secretion by the parathyroid glands (6, 7, 8). Thus, its net effect is a reduction in serum phosphate and 1,25(OH)2D levels, which may result in hypocalcemia.

Increased serum FGF23 concentrations were an independent predictor of coronary artery disease in patients with mild chronic kidney disease and mortality in patients undergoing hemodialysis (9, 10). Recently, FGF23 has been found to be associated with total body atherosclerosis and vascular dysfunction (11, 12). However, another study found that circulating FGF23 did not correlate with coronary artery calcification in patients with normal renal function (13). In men and women with cardiovascular disease, increased levels of FGF23 were an independent predictor of cardiac events (14). Elevated FGF23 levels have been associated with left ventricular hypertrophy (15, 16).

The relationship between FGF23 and cardiovascular disease in the general population has not been characterized. The specific aim of this study was to determine whether elevated serum FGF23 concentrations are associated with cardiovascular disease. To address this aim, we examined the relationship between serum FGF23 and prevalent cardiovascular disease in older women living in the community.

Materials and methods

Participants

A cross-sectional study was conducted among 659 women, from the Women's Health and Aging Studies (WHAS) I and II, two population-based cohorts of community-dwelling women living in Baltimore, Maryland. Both cohorts were designed to investigate factors associated with the progression of physical disability. WHAS I, which consisted of 1002 women aged 65 and older, represented one-third of the most disabled women living in Baltimore. WHAS II was composed of 436 women aged 70–79 recruited from among the two-thirds least disabled in the same community. This study involved 299 women, age 70–79 years, from WHAS I, and 360 women from WHAS II.

Participants were recruited from an age-stratified random sample of women aged 65 years and older selected from Medicare enrollees residing in 12 contiguous zip code areas in eastern Baltimore city and Baltimore County. Baseline assessment occurred from November 1992 to February 1995 in WHAS I and from August 1994 to February 1996 in WHAS II. Standardized questionnaires, a physical examination, and a physical performance testing were administered by trained interviewers the participant's home in WHAS I and in the Johns Hopkins Functional Laboratory in WHAS II. Body mass index was calculated as weight/height2 (kg/m2). Mini-Mental State Examination (MMSE) was recorded (17). Chronic kidney disease was defined as estimated glomerular filtration rate of <60 ml/min per 1.73 m2 using the four-variable Modification of Diet in Renal Disease Study (MDRD) equation of Levey et al. (18). Race was assessed in a questionnaire as black, white, or other, current smoking as yes or no, and education as 0–8, 9–11, 12 years or more than 12 years as the highest level of formal education achieved. Chronic diseases were adjudicated by WHAS co-investigators based on standardized questionnaires, physical examination, physician contact, and diagnostic algorithms. Further details on the methods and sampling design of the WHAS studies are published elsewhere (19, 20). Cardiovascular disease was defined as a combination of any of these adjudicated conditions: coronary artery disease, congestive heart failure, stroke, and peripheral artery disease. Written informed consent was obtained from all participants. The study protocol complied with the Declaration of Helsinki. The Johns Hopkins Medical Institutions Institutional Review Board approved the research protocols.

Laboratory measurements

Non-fasting blood specimens were collected at the participants' homes in WHAS I and at the Johns Hopkins General Clinical Research Center in WHAS II. Total cholesterol and high-density lipoprotein (HDL) cholesterol were measured by enzymatic methods at Quest Diagnostics. Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald equation (21). Active intact full-length FGF23 was measured in previously unthawed serum samples collected at baseline using a commercial sandwich ELISA according to the manufacturer's protocol (Kainos Laboratories, Inc., Tokyo, Japan). This ELISA utilizes two murine MABs for two separate sites (22). In this study, the intra- and inter-assay coefficients of variation were 2.8 and 4.9% respectively.

Statistical analysis

Variables are reported as medians (25th, 75th percentiles) or as percentages. Characteristics of subjects were compared across tertiles of serum FGF23 and according to cardiovascular disease by Kruskal–Wallis rank sum tests for continuous variables and χ2 tests for categorical variables. Bivariate and multivariable logistic regression models were used to examine the relationship between serum FGF23 and cardiovascular disease. Variables that were significantly associated with cardiovascular disease or tertiles of FGF23 in the bivariate analyses and total and HDL cholesterol were entered into the multivariable analyses. All analyses were performed by SAS (v. 9.1.3, SAS Institute, Inc., Cary, NC, USA). The level of significance used in this study was P<0.05.

Results

Serum FGF23 concentrations were skewed in distribution. Overall, the mean (s.d.) of log serum FGF23 concentration (pg/ml) was 3.52 (0.52) and median (25th, 75th percentile) serum FGF23 was 34.6 (25.2, 46.2) pg/ml. The health and demographic characteristics of the 659 women across tertiles of serum FGF23 concentrations are shown in Table 1. Higher serum FGF23 concentrations were associated with older age, higher body mass index, greater education, lower physical activity, and lower estimated glomerular filtration rate; hypertension, coronary artery disease, peripheral artery disease, and cardiovascular disease. There were no significant differences across the tertiles of serum FGF23 concentrations by race, alcohol intake, current smoking, cognitive impairment, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, or by the prevalence of congestive heart failure, stroke, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, depression, and cancer. The proportion of participants who had cardiovascular disease was highest in the highest tertile and lowest in the lowest tertile of serum FGF23 (P=0.002).

Table 1

Characteristics of 659 women, aged 70–79 years, in the WHAS, by tertiles of serum FGF23.

Tertile of serum FGF23 (pg/ml)
Characteristics<28.1 (n=221)28.1–42.4 (n=217)>42.4 (n=221)P
Age (years)73 (71, 76)74 (72, 77)74 (71, 76)0.009
Race, white (%)77.473.777.00.62
Education <12 years (%)77.068.161.00.001
Uses alcohol (%)25.823.026.00.74
Smoking (%)0.55
 Never47.554.046.4
 Former39.835.041.4
 Current12.711.512.3
BMI (kg/m2)26.1 (22.1, 30.6)26.6 (23.3, 30.1)28.1 (24.6, 31.0)0.002
Physical activity (%)<0.0001
 Low41.954.764.2
 Medium27.215.615.6
 High30.929.820.3
MMSE score <24 (%)5.97.47.30.79
Cholesterol (mg/dl)
 Total228 (202, 256)230 (207, 257)226 (203, 254)0.61
 HDL55 (45, 66)54 (44, 66)51 (43, 63)0.16
 LDL (mg/dl)140 (118, 163)141 (117, 166)138 (116, 164)0.98
Triglycerides (mg/dl)132 (89, 207)141 (98, 199)140 (96, 203)0.67
SBP (mmHg)145.0 (131.5, 163.0)144.0 (130.0, 159.0)145.5 (130.0, 160.0)0.75
DBP (mmHg)70.5 (63.0, 80.0)70.0 (61.0, 80.0)69.0 (62.0, 79.0)0.49
Estimated GFR (ml/min per 1.73 m2)62.9 (51.7, 74.3)61.9 (51.7, 70.3)57.6 (51.1, 65.8)0.05
Hypertension (%)44.351.261.40.001
Coronary artery disease (%)12.213.421.30.02
Congestive heart failure (%)5.04.68.60.15
Peripheral artery disease (%)8.13.817.20.02
Stroke (%)2.72.34.50.37
Cardiovascular disease (%)a22.624.936.70.002
Diabetes mellitus (%)13.19.716.30.12
COPD (%)26.728.124.40.68
Chronic kidney disease (%)49.149.356.90.20
Depression (%)18.819.814.40.51
Cancer (%)9.19.710.90.81

HDL, high-density lipoprotein; LDL, low-density lipoprotein; GFR, glomerular filtration rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; COPD, chronic obstructive pulmonary disease.

Coronary heart disease, congestive heart failure, peripheral artery disease, and stroke.

Of the 659 women, 185 (28.1%) had cardiovascular disease. The demographic and health characteristics of women according to the diagnosis of cardiovascular disease are shown in Table 2. Serum FGF23 was significantly higher in adults with than those without cardiovascular disease (P=0.0001). Participants who had cardiovascular disease were more likely to be white, current smokers, less active, with cognitive impairment, and with hypertension; coronary artery disease, congestive heart failure, peripheral artery disease, stroke, and diabetes mellitus. There were no significant differences between participants who had cardiovascular disease by age, education level, alcohol use, body mass index, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, estimated glomerular filtration rate, chronic obstructive pulmonary disease, chronic kidney disease, depression, and cancer.

Table 2

Characteristics of 659 women, aged 70–79 years, in the WHAS, with or without CVD. Numbers in parentheses indicate 25th, 75th percentile.

With CVD (n=185)Without CVD (n=474)
Characteristicsn% or mediann% or medianP
Age (years)18574 (71, 77)47474 (72, 76)0.44
Race, white (%)12668.137579.10.003
Education <12 years (%)11863.833370.60.09
Uses alcohol (%)3820.512626.6 0.10
Smoking (%)0.007
 Never7339.525153.1
 Former8445.417036.0
 Current2815.15211.0
BMI (kg/m2)17127.6 (23.6, 31.4)45826.8 (23.1, 30.5)0.20
Physical activity0.0002
 Low11465.122949.1
 Medium3318.99219.7
 High2816.014531.1
MMSE score <24 (%)2211.9234.90.001
Cholesterol (mg/dl)
 Total169228 (199, 256)448229 (206, 254)0.39
 HDL17252.0 (43.0, 62.0)45154.0 (44.0, 66.0)0.17
 LDL169138 (115, 162)448139 (118, 166)0.54
Triglycerides (mg/dl)169141 (100, 202)448137 (92, 203)0.68
Log serum FGF23 (pg/ml)1853.7 (3.3, 4.0)4743.5 (3.2, 3.8)0.0001
SBP (mmHg)185143.0 (129.0, 160.0)474146.0 (131.0, 160.0)0.25
DBP (mmHg)18567.0 (60.0, 74.0)47472.0 (64.0, 81.0)<0.0001
Estimated GFR (ml/min per 1.73 m2)16957.7 (47.2, 69.9)44858.3 (51.7, 70.4)0.18
Hypertension (%)11964.322547.6 0.0001
Diabetes mellitus (%)4524.3418.7<0.0001
COPD (%)5328.712125.50.41
Chronic kidney disease (%)9355.022650.50.31
Depression (%)2418.32716.10.61
Cancer (%)189.7479.90.94

HDL, high-density lipoprotein; LDL, low-density lipoprotein; GFR, glomerular filtration rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; COPD, chronic obstructive pulmonary disease.

The relationship between serum FGF23 and cardiovascular disease was examined using separate multivariable logistic regression models for all participants (Table 3). Higher serum FGF23 was associated with increased odds of cardiovascular disease after adjusting for age, race, smoking, education, body mass index, cognition, diabetes mellitus, hypertension, and physical activity (P<0.0001). In another model with additional adjustment for total cholesterol, HDL cholesterol, and renal function, the association between serum FGF23 and cardiovascular disease was nearly unchanged (P<0.0001).

Table 3

Multivariate logistic regression models of the relationship between serum FGF23 and cardiovascular disease in 659 women, aged 70–79 years, in the WHAS, for all participants and stratified by chronic kidney disease at baselinea.

Model 1bModel 2cModel 3d
OR95% CIPOR95% CIPOR95% CIP
All participants1.261.20, 1.33<0.00011.231.16, 1.30<0.00011.241.18, 1.31<0.0001
Chronic kidney diseasee
 Absent1.141.05, 1.240.0011.101.01, 1.190.041.101.01, 1.200.03
 Present1.411.30, 1.53<0.00011.421.31, 1.55<0.00011.441.32, 1.57<0.0001

Odds ratio (OR) expressed per 1 s.d. of log serum FGF23 (1 s.d.=0.52 pg/ml).

Model 1 – adjusted for age, race, smoking, education, body mass index, MMSE, diabetes, and hypertension.

Model 2 – adjusted for age, race, smoking, education, body mass index, MMSE, diabetes, hypertension, and physical activity.

Model 3 – adjusted for age, race, smoking, education, body mass index, cognition, diabetes, hypertension, physical activity, total cholesterol, HDL cholesterol,  and renal function.

For analyses stratified by chronic kidney disease, Model 3 includes all covariates above except renal function.

The relationship between serum FGF23 and cardiovascular disease was examined in additional separate multivariable logistic regression models that were stratified by the presence or absence of chronic kidney disease at baseline. In women without chronic kidney disease, higher serum FGF23 was associated with increased odds of cardiovascular disease in multivariable models after adjusting for age, race, smoking, education, body mass index, cognition, diabetes mellitus, hypertension, physical activity, total cholesterol, and HDL cholesterol (Table 3). The magnitude of the odds ratio (OR) was higher in the final model for women with chronic kidney disease compared with those without chronic kidney disease (OR 1.44 vs 1.10 respectively).

Alternative multivariable models were used to examine the relationship between tertiles of serum FGF23 and cardiovascular disease. Women in the highest and middle tertiles of FGF23, respectively, had a high odds of cardiovascular disease compared with those in the lowest tertile after adjusting for age, race, smoking, education, body mass index, cognition, diabetes mellitus, and hypertension (OR 1.57, 95% confidence interval (CI) 1.38, 1.78; OR 0.88, 95% CI 0.77, 1.01), additionally for physical activity (OR 1.52, 95% CI 1.33, 1.73; OR 0.89, 95% CI 0.78, 1.02), and finally with addition of total cholesterol and HDL cholesterol to the model (OR 1.49, 95% CI 1.30, 1.70; OR 0.91, 95% CI 0.79, 1.05).

Discussion

This study demonstrates that older community-dwelling women, aged 70–79 years, with high serum FGF23 concentrations have higher odds of cardiovascular disease. To our knowledge, this is the first study to show that high serum FGF23 concentrations are independently associated with cardiovascular disease in the general population. This finding is consistent with previous reports that have shown increased levels of FGF23 are an independent risk factor for cardiovascular disease and adverse cardiovascular events (11, 12, 13). Currently, there are two types of assays for measuring circulating FGF23. In this study, we measured intact FGF23, in contrast to assays that measure the inactive C-terminal fragment. Many studies have shown a high correlation between the two assays (23).

The potential role of FGF23 in the pathogenesis of cardiovascular disease may be partly explained through its involvement in the complex process of vascular calcification. Vascular calcification involves complex interplay between calcification stimulators and inhibitors, key players being hyperphosphatemia and increased levels of parathyroid hormone and vitamin D (24). Increased phosphate levels, parathyroid hormone, and 1,25(OH)2D3 are all independently associated with cardiovascular-related morbidity and mortality (25, 26, 27). Higher levels of FGF23 are also associated with the development of coronary artery calcification, especially in the presence of chronic kidney disease (28). Since FGF23 is a known regulator of all three factors, it is plausible to that FGF23 could be involved in the mechanism of vascular calcification. FGF23 has also been implicated in the development of left ventricular hypertrophy in older community-dwelling adults (15) and in patients with chronic kidney disease (16), which may help explain the association between elevated FGF23 and prevalent cardiovascular disease.

The observed role of FGF23 in vascular calcification may be explained by the role of klotho as an important co-factor for FGF23, without which FGF23 bioactivity declines (29). Inactivating mutations in the klotho gene in mice show premature aging phenotypes including hyperphosphatemia, extensive vascular calcification, atherosclerosis, and increased levels of vitamin D, which are also shared by FGF23-null mice (4, 30). In humans, previous studies have shown that decreased plasma α-klotho concentrations are associated with vascular calcification and independently predict longevity and mortality (31, 32). Consequently, excess FGF23 levels with declining klotho levels may be a result of unresolved hyperphosphatemia and abnormal vitamin D metabolism, which are also important factors in vascular calcification (23). Coronary artery calcification is a strong predictor of cardiac events and all-cause mortality in healthy older adults (33, 34). Thus, FGF23 may be an important biomarker for the development and progression of vascular calcification and the pathogenesis of cardiovascular disease.

There are several limitations of the study including the use of the MDRD Study equation, which has not yet been validated in adults >70 years of age. The study was conducted in only community-dwelling women, 70 to 79 years old, and the present findings cannot therefore be generalized to older men. Residual confounding by other factors such as serum phosphate and vitamin D levels could be a potential limitation. Further prospective studies are needed in other populations to determine if elevated FGF23 levels are predictive of incident cardiovascular disease and to further elucidate the potential role of FGF23 in the pathogenesis of cardiovascular disease. A recent nested case–control study showed that in the Health Professionals Follow-Up Study, a prospective cohort involving male health professionals, aged 40–75 years, with normal renal function, plasma FGF23 was not an independent predictor of incident coronary heart disease (35). This cohort involved men with normal kidney function without cardiovascular disease at baseline. It may be possible that FGF23 is associated with severity but not the incidence of cardiovascular disease or that elevated FGF23 is primarily a risk factor for cardiovascular disease in adults with impaired renal function. In addition, the 10-year follow-up interval between baseline and incident cardiovascular disease may have attenuated the risk magnitude associated with a single measure of FGF23 (35).

In conclusion, this study demonstrates that FGF23 is associated with prevalent cardiovascular disease in older, community-dwelling women. Further studies are needed to elucidate the potential biological mechanisms by which FGF23 may be involved in the pathogenesis of cardiovascular disease.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was supported by National Institute on Aging Grants R01 AG027012 and R01 HL094507, R37 AG019905, OPD-GCRC grant RR00722 and NIA Contract N01-AG12112, the Johns Hopkins Older Americans' Independence Center, and the Intramural Research Program, National Institute on Aging, NIH.

Author contribution statement

We confirm that all of the named authors contributed substantially to the article and agreed to take public responsibility for the validity of its content.

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    Dhingra R, Sullivan LM, Fox CS, Wang TJ, D'Agostino RB Sr, Gaziano JM, Vasan RS. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Archives of Internal Medicine 2007 167 879885. doi:10.1001/archinte.167.9.879.

    • Search Google Scholar
    • Export Citation
  • 26

    Kamycheva E, Sundsfjord J, Jorde R. Serum parathyroid hormone levels predict coronary heart disease: the Tromsø Study. European Journal of Cardiovascular Prevention and Rehabilitation 2004 11 6974. doi:10.1097/01.hjr.0000114706.27531.01.

    • Search Google Scholar
    • Export Citation
  • 27

    Ginde AA, Scragg R, Schwartz RS, Camargo CA Jr. Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults. Journal of the American Geriatrics Society 2009 57 15951603. doi:10.1111/j.1532-5415.2009.02359.x.

    • Search Google Scholar
    • Export Citation
  • 28

    Balci M, Kirkpantur A, Gulbay M, Gurbuz OA. Plasma fibroblast growth factor-23 levels are independently associated with carotid artery atherosclerosis in maintenance hemodialysis patients. Hemodialysis International 2010 14 425432. doi:10.1111/j.1542-4758.2010.00480.x.

    • Search Google Scholar
    • Export Citation
  • 29

    Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006 444 770774. doi:10.1038/nature05315.

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    • Export Citation
  • 30

    Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997 390 4551. doi:10.1038/36285.

    • Search Google Scholar
    • Export Citation
  • 31

    Hu MC, Shi M, Zhang J, Quiñones H, Griffith C, Kuro-o M, Moe OW. Klotho deficiency causes vascular calcification in chronic kidney disease. Journal of the American Society of Nephrology 2011 22 124136. doi:10.1681/ASN.2009121311.

    • Search Google Scholar
    • Export Citation
  • 32

    Semba RD, Cappola AR, Sun K, Bandinelli S, Dalal M, Crasto C, Guralnik JM, Ferrucci L. Plasma klotho and mortality risk in older community-dwelling adults. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2011 66 794800. doi:10.1093/gerona/glr058.

    • Search Google Scholar
    • Export Citation
  • 33

    LaMonte MJ, FitzGerald SJ, Church TS, Barlow CE, Radford NB, Levine BD, Pippin JJ, Gibbons LW, Blair SN, Nichaman MZ. Coronary artery calcium score and coronary heart disease events in a large cohort of asymptomatic men and women. American Journal of Epidemiology 2005 162 421429. doi:10.1093/aje/kwi228.

    • Search Google Scholar
    • Export Citation
  • 34

    Raggi P, Gongora MC, Gopal A, Callister TQ, Budoff M, Shaw LJ. Coronary artery calcium to predict all-cause mortality in elderly men and women. Journal of the American College of Cardiology 2008 52 1723. doi:10.1016/j.jacc.2008.04.004.

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    • Export Citation
  • 35

    Taylor EN, Rimm EB, Stampfer MJ, Curhan GC. Plasma fibroblast growth factor 23, parathyroid hormone, phosphorus, and risk of coronary heart disease. American Heart Journal 2011 161 956962. doi:10.1016/j.ahj.2011.02.012.

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     European Society of Endocrinology

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  • 1

    Palmer SC, Hayen A, Macaskill P, Pellegrini F, Craig JC, Elder GJ, Strippoli GF. 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. Journal of the American Medical Association 2011 305 11191127. doi:10.1001/jama.2011.308.

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  • 2

    Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. Journal of the American Society of Nephrology 2004 15 22082218. doi:10.1097/01.ASN.0000133041.27682.A2.

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  • 3

    Covic A, Kothawala P, Bernal M, Robbins S, Chalian A, Goldsmith D. Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease. Nephrology, Dialysis, Transplantation 2009 24 15061523. doi:10.1093/ndt/gfn613.

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  • 4

    Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. Journal of Clinical Investigation 2004 113 561568. doi:10.1172/JCI19081.

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  • 5

    Vervloet MG, van Ittersum FJ, Büttler RM, Heijboer AC, Blankenstein MA, ter Wee PM. Effects of dietary phosphate and calcium intake on fibroblast growth factor-23. Clinical Journal of the American Society of Nephrology 2011 6 383389. doi:10.2215/CJN.04730510.

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  • 6

    Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, Mohammadi M, Baum M. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. American Journal of Physiology. Renal Physiology 2009 297 F282F291. doi:10.1152/ajprenal.90742.2008.

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  • 7

    Razzaque MS, Lanske B. The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis. Journal of Endocrinology 2007 194 110. doi:10.1677/JOE-07-0095.

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  • 8

    Kanbay M, Nicoleta M, Selcoki Y, Ikizek M, Aydin M, Eryonucu B, Duranay M, Akcay A, Armutcu F, Covic A. Fibroblast growth factor 23 and fetuin A are independent predictors for the coronary artery disease extent in mild chronic kidney disease. Clinical Journal of the American Society of Nephrology 2010 5 17801786. doi:10.2215/CJN.02560310.

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  • 9

    Gutiérrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Jüppner H, Wolf M. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. New England Journal of Medicine 2008 359 584592. doi:10.1056/NEJMoa0706130.

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  • 10

    Jean G, Terrat JC, Vanel T, Hurot JM, Lorriaux C, Mayor B, Chazot C. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrology, Dialysis, Transplantation 2009 24 27922796. doi:10.1093/ndt/gfp191.

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  • 11

    Mirza MA, Hansen T, Johansson L, Ahlström H, Larsson A, Lind L, Larsson TE. Relationship between circulating FGF23 and total body atherosclerosis in the community. Nephrology, Dialysis, Transplantation 2009 24 31253131. doi:10.1093/ndt/gfp205.

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  • 12

    Mirza MA, Larsson A, Lind L, Larsson TE. Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. Atherosclerosis 2009 205 385390. doi:10.1016/j.atherosclerosis.2009.01.001.

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  • 13

    Roos M, Lutz J, Salmhofer H, Luppa P, Knauss A, Braun S, Martinof S, Schömig A, Heemann U, Kastrati A, Hausleiter J. Relation between plasma fibroblast growth factor-23, serum fetuin-A levels and coronary artery calcification evaluated by multislice computed tomography in patients with normal kidney function. Clinical Endocrinology 2008 68 660665. doi:10.1111/j.1365-2265.2007.03074.x.

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  • 14

    Parker BD, Schurgers LJ, Brandenburg VM, Christenson RH, Vermeer C, Ketteler M, Shlipak MG, Whooley MA, Ix J. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Annals of Internal Medicine 2010 152 640648.

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  • 15

    Mirza MA, Larsson A, Melhus H, Lind L, Larsson TE. Serum intact FGF23 associated with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis 2009 207 541551. doi:10.1016/j.atherosclerosis.2009.05.013.

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  • 16

    Canziani ME, Tomiyama C, Higa A, Draibe SA, Carvalho AB. Fibroblast growth factor 23 in chronic kidney disease: bridging the gap between bone mineral metabolism and left ventricular hypertrophy. Blood Purification 2011 31 2632. doi:10.1159/000321368.

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    Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State” a practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 1975 12 189198. doi:10.1016/0022-3956(75)90026-6.

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    Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Annals of Internal Medicine 1999 130 461470.

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  • 19

    Guralnik JM, Fried LP, Simonsick EM, Kasper JD & Lafferty ME, eds. The Women's Health and Aging Study: Health and Social Characteristics of Older Women with Disability. Bethesda, MD: National Institute on Aging, 1995; NIH Pub. No. 95-4009.

  • 20

    Fried LP, Bandeen-Roche K, Chaves PH, Johnson BA. Preclinical mobility disability predicts incident mobility disability in older women. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2000 55 M43M52. doi:10.1093/gerona/55.1.M43.

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  • 21

    Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density-lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical Chemistry 1972 18 499502.

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  • 22

    Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, Takeuchi Y, Fujita T, Nakahara K, Yamashita T, Fukumoto S. Increased circulatory level of biologically active full-length FGF23 in patients with hypophosphatemic rickets/osteomalacia. Journal of Clinical Endocrinology and Metabolism 2002 87 49574960. doi:10.1210/jc.2002-021105.

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  • 23

    Wolf M. Forging forward with 10 burning questions on FGF23 in kidney disease. Journal of the American Society of Nephrology 2010 21 14271435. doi:10.1681/ASN.2009121293.

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  • 24

    Covic A, Kanbay M, Voroneanu L, Turgut F, Serban DN, Serban IL, Goldsmith DJ. Vascular calcification in chronic kidney disease. Clinical Science 2010 119 111121. doi:10.1042/CS20090631.

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  • 25

    Dhingra R, Sullivan LM, Fox CS, Wang TJ, D'Agostino RB Sr, Gaziano JM, Vasan RS. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Archives of Internal Medicine 2007 167 879885. doi:10.1001/archinte.167.9.879.

    • Search Google Scholar
    • Export Citation
  • 26

    Kamycheva E, Sundsfjord J, Jorde R. Serum parathyroid hormone levels predict coronary heart disease: the Tromsø Study. European Journal of Cardiovascular Prevention and Rehabilitation 2004 11 6974. doi:10.1097/01.hjr.0000114706.27531.01.

    • Search Google Scholar
    • Export Citation
  • 27

    Ginde AA, Scragg R, Schwartz RS, Camargo CA Jr. Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults. Journal of the American Geriatrics Society 2009 57 15951603. doi:10.1111/j.1532-5415.2009.02359.x.

    • Search Google Scholar
    • Export Citation
  • 28

    Balci M, Kirkpantur A, Gulbay M, Gurbuz OA. Plasma fibroblast growth factor-23 levels are independently associated with carotid artery atherosclerosis in maintenance hemodialysis patients. Hemodialysis International 2010 14 425432. doi:10.1111/j.1542-4758.2010.00480.x.

    • Search Google Scholar
    • Export Citation
  • 29

    Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006 444 770774. doi:10.1038/nature05315.

    • Search Google Scholar
    • Export Citation
  • 30

    Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997 390 4551. doi:10.1038/36285.

    • Search Google Scholar
    • Export Citation
  • 31

    Hu MC, Shi M, Zhang J, Quiñones H, Griffith C, Kuro-o M, Moe OW. Klotho deficiency causes vascular calcification in chronic kidney disease. Journal of the American Society of Nephrology 2011 22 124136. doi:10.1681/ASN.2009121311.

    • Search Google Scholar
    • Export Citation
  • 32

    Semba RD, Cappola AR, Sun K, Bandinelli S, Dalal M, Crasto C, Guralnik JM, Ferrucci L. Plasma klotho and mortality risk in older community-dwelling adults. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2011 66 794800. doi:10.1093/gerona/glr058.

    • Search Google Scholar
    • Export Citation
  • 33

    LaMonte MJ, FitzGerald SJ, Church TS, Barlow CE, Radford NB, Levine BD, Pippin JJ, Gibbons LW, Blair SN, Nichaman MZ. Coronary artery calcium score and coronary heart disease events in a large cohort of asymptomatic men and women. American Journal of Epidemiology 2005 162 421429. doi:10.1093/aje/kwi228.

    • Search Google Scholar
    • Export Citation
  • 34

    Raggi P, Gongora MC, Gopal A, Callister TQ, Budoff M, Shaw LJ. Coronary artery calcium to predict all-cause mortality in elderly men and women. Journal of the American College of Cardiology 2008 52 1723. doi:10.1016/j.jacc.2008.04.004.

    • Search Google Scholar
    • Export Citation
  • 35

    Taylor EN, Rimm EB, Stampfer MJ, Curhan GC. Plasma fibroblast growth factor 23, parathyroid hormone, phosphorus, and risk of coronary heart disease. American Heart Journal 2011 161 956962. doi:10.1016/j.ahj.2011.02.012.

    • Search Google Scholar
    • Export Citation