@article {1392, title = {Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study).}, journal = {J Am Coll Cardiol}, volume = {60}, year = {2012}, month = {2012 Jul 17}, pages = {200-7}, abstract = {

OBJECTIVES: This study sought to determine the association of fibroblast growth factor (FGF)-23 with death, heart failure (HF), and cardiovascular disease (CVD) in the general population, as well as the influence of chronic kidney disease (CKD) in this setting.

BACKGROUND: FGF-23 increases renal phosphorus excretion and inhibits vitamin D activation. In end-stage renal disease, high FGF-23 levels are associated with mortality. The association of FGF-23 with death, HF, and CVD in the general population, and the influence of CKD in this setting, are unknown.

METHODS: Plasma FGF-23 was measured in 3,107 community-living persons >= 65 years of age in 1996 and 1997, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF-23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status.

RESULTS: Both lower estimated glomerular filtration rate and higher urine albumin to creatinine ratios were associated with high FGF-23 at baseline. During 10.5 years (median) follow-up, there were 1,730 deaths, 697 incident HF events, and 797 incident CVD events. Although high FGF-23 concentrations were associated with each outcome in combined analyses, the associations were consistently stronger for those with CKD (p interactions all <0.006). In the CKD group (n = 1,128), the highest FGF-23 quartile had adjusted hazards ratios (HR) of 1.87 (95\% confidence interval [CI]: 1.47 to 2.38) for all-cause death, 1.94 (95\% CI: 1.32 to 2.83) for incident HF, and 1.49 (95\% CI: 1.02 to 2.18) for incident CVD events compared with the lowest quartile. Corresponding HRs in those without CKD (n = 1,979) were 1.29 (95\% CI: 1.05 to 1.59), 1.37 (95\% CI: 0.99 to 1.89), and 1.07 (95\% CI: 0.79 to 1.45).

CONCLUSIONS: FGF-23, a hormone involved in phosphorous and vitamin D homeostasis, is independently associated with all-cause death and incident HF in community-living older persons. These associations appear stronger in persons with CKD.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Female, Fibroblast Growth Factors, Heart Failure, Humans, Kidney Function Tests, Male, Mortality, Renal Insufficiency, Chronic, United States}, issn = {1558-3597}, doi = {10.1016/j.jacc.2012.03.040}, author = {Ix, Joachim H and Katz, Ronit and Kestenbaum, Bryan R and de Boer, Ian H and Chonchol, Michel and Mukamal, Kenneth J and Rifkin, Dena and Siscovick, David S and Sarnak, Mark J and Shlipak, Michael G} } @article {5996, title = {Fibroblast growth factor 23, bone mineral density, and risk of hip fracture among older adults: the cardiovascular health study.}, journal = {J Clin Endocrinol Metab}, volume = {98}, year = {2013}, month = {2013 Aug}, pages = {3323-31}, abstract = {

CONTEXT: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that also inhibits calcitriol synthesis.

OBJECTIVE: Our objective was to evaluate the relationships of plasma FGF23 concentrations with bone mineral density (BMD) and hip fracture in community-dwelling older adults.

DESIGN AND SETTING: Linear regression and Cox proportional hazard models were used to examine the associations of plasma FGF23 concentrations with BMD and incident hip fracture, respectively. Analyses were also stratified by chronic kidney disease.

PARTICIPANTS: Participants included 2008 women and 1329 men >=65 years from the 1996 to 1997 Cardiovascular Health Study visit.

MAIN OUTCOME MEASURES: Dual x-ray absorptiometry measured total hip (TH) and lumbar spine (LS) BMD in 1291 participants. Hip fracture incidence was assessed prospectively through June 30, 2008 by hospitalization records in all participants.

RESULTS: Women had higher plasma FGF23 concentrations than men (75 [56-107] vs 66 [interquartile range = 52-92] relative units/mL; P < .001). After adjustment, higher FGF23 concentrations were associated with greater total hip and lumbar spine BMD in men only (β per doubling of FGF23 = 0.02, with 95\% confidence interval [CI] = 0.001-0.04 g/cm(2), and 0.03 with 95\% CI = 0.01-0.06 g/cm(2)). During 9.6 {\textpm} 5.1-11.0 years of follow-up, 328 hip fractures occurred. Higher FGF23 concentrations were not associated with hip fracture risk in women or men (adjusted hazard ratio = 0.95, with 95\% CI = 0.78-1.15, and 1.09 with 95\% CI = 0.82-1.46 per doubling of FGF23). Results did not differ by chronic kidney disease status (P > .4 for interactions).

CONCLUSIONS: In this large prospective cohort of community-dwelling older adults, higher FGF23 concentrations were weakly associated with greater lumbar spine and total hip BMD but not with hip fracture risk.

}, keywords = {Aged, Aged, 80 and over, Bone Density, Female, Fibroblast Growth Factors, Hip Fractures, Humans, Longitudinal Studies, Male, Middle Aged, Prospective Studies, Risk, Spinal Fractures}, issn = {1945-7197}, doi = {10.1210/jc.2013-1152}, author = {Jovanovich, Anna and B{\r u}zkov{\'a}, Petra and Chonchol, Michel and Robbins, John and Fink, Howard A and de Boer, Ian H and Kestenbaum, Bryan and Katz, Ronit and Carbone, Laura and Lee, Jennifer and Laughlin, Gail A and Mukamal, Kenneth J and Fried, Linda F and Shlipak, Michael G and Ix, Joachim H} } @article {7379, title = {Fibroblast growth factor 23, left ventricular mass, and left ventricular hypertrophy in community-dwelling older adults.}, journal = {Atherosclerosis}, volume = {231}, year = {2013}, month = {2013 Nov}, pages = {114-9}, abstract = {

OBJECTIVES: In chronic kidney disease (CKD), high FGF23 concentrations are associated with left ventricular hypertrophy (LVH), cardiovascular events, and death. The associations of FGF23 with left ventricular mass (LVM) and LVH in the general population and the influence of CKD remains uncertain.

METHODS: C-terminal plasma FGF23 concentrations were measured, and LVM and LVH evaluated by echocardiogram among 2255 individuals >=65 years in the Cardiovascular Health Study. Linear regression analysis adjusting for demographics, cardiovascular, and kidney related risk factors examined the associations of FGF23 concentrations with LVM. Analyses were stratified by CKD status and adjusted linear and logistic regression analysis explored the associations of FGF23 with LVM and LVH.

RESULTS: Among the entire cohort, higher FGF23 concentrations were associated with greater LVM in adjusted analyses (β = 6.71 [95\% CI 4.35-9.01] g per doubling of FGF23). 32\% (n = 624) had CKD (eGFR <60 mL/min/1.73 m(2) and/or urine albumin-to-creatinine ratio >30 mg/g). Associations were stronger among participants with CKD (p interaction = 0.006): LVM β = 9.71 [95\% CI 5.86-13.56] g per doubling of FGF23 compared to those without CKD (β = 3.44 [95\% CI 0.77, 6.11] g per doubling of FGF23). While there was no significant interaction between FGF23 and CKD for LVH (p interaction = 0.25), the OR (1.46 95\% CI [1.20-1.77]) in the CKD group was statistically significant and of larger magnitude than the OR for in the no CKD group (1.12 [95\% CI 0.97-1.48]).

CONCLUSION: In a large cohort of older community-dwelling adults, higher FGF23 concentrations were associated with greater LVM and LVH with stronger relationships in participants with CKD.

}, keywords = {Aged, Female, Fibroblast Growth Factors, Heart Ventricles, Humans, Hypertrophy, Left Ventricular, Longitudinal Studies, Male, Renal Insufficiency, Chronic, Risk Factors, Ultrasonography}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2013.09.002}, author = {Jovanovich, Anna and Ix, Joachim H and Gottdiener, John and McFann, Kim and Katz, Ronit and Kestenbaum, Bryan and de Boer, Ian H and Sarnak, Mark and Shlipak, Michael G and Mukamal, Kenneth J and Siscovick, David and Chonchol, Michel} } @article {6239, title = {Fibroblast growth factor 23, the ankle-brachial index, and incident peripheral artery disease in the Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {233}, year = {2014}, month = {2014 Mar}, pages = {91-6}, abstract = {

BACKGROUND: Fibroblast growth factor 23 (FGF23) has emerged as a novel risk factor for mortality and cardiovascular events. Its association with the ankle-brachial index (ABI) and clinical peripheral artery disease (PAD) is less known.

METHODS: Using data (N = 3143) from the Cardiovascular Health Study (CHS), a cohort of community dwelling adults >65 years of age, we analyzed the cross-sectional association of FGF23 with ABI and its association with incident clinical PAD events during 9.8 years of follow up using multinomial logistic regression and Cox proportional hazards models respectively.

RESULTS: The prevalence of cardiovascular disease (CVD) and traditional risk factors like diabetes, coronary artery disease, and heart failure increased across higher quartiles of FGF23. Compared to those with ABI of 1.1-1.4, FGF23 per doubling at baseline was associated with prevalent PAD (ABI < 0.9) although this association was attenuated after adjusting for CVD risk factors, and kidney function (OR 0.91, 95\% CI 0.76-1.08). FGF23 was not associated with high ABI (>1.4) (OR 1.06, 95\% CI 0.75-1.51). Higher FGF23 was associated with incidence of PAD events in unadjusted, demographic adjusted, and CVD risk factor adjusted models (HR 2.26, 95\% CI 1.28-3.98; highest versus lowest quartile). The addition of estimated glomerular filtration and urine albumin to creatinine ratio to the model however, attenuated these findings (HR 1.46, 95\% CI, 0.79-2.70).

CONCLUSIONS: In community dwelling older adults, FGF23 was not associated with baseline low or high ABI or incident PAD events after adjusting for confounding variables. These results suggest that FGF23 may primarily be associated with adverse cardiovascular outcomes through non atherosclerotic mechanisms.

}, keywords = {Aged, Ankle Brachial Index, Cardiovascular Diseases, Cross-Sectional Studies, Fibroblast Growth Factors, Humans, Incidence, Peripheral Arterial Disease, Risk Factors}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2013.12.015}, author = {Garimella, Pranav S and Ix, Joachim H and Katz, Ronit and Chonchol, Michel B and Kestenbaum, Bryan R and de Boer, Ian H and Siscovick, David S and Shastri, Shani and Hiramoto, Jade S and Shlipak, Michael G and Sarnak, Mark J} } @article {6308, title = {Fibroblast growth factor-23 and the long-term risk of hospital-associated AKI among community-dwelling older individuals.}, journal = {Clin J Am Soc Nephrol}, volume = {9}, year = {2014}, month = {2014 Feb}, pages = {239-46}, abstract = {

BACKGROUND AND OBJECTIVES: AKI occurs frequently in older persons. Elevated circulating fibroblast growth factor-23 (FGF-23), a known marker of impaired mineral metabolism, may also reflect tubular dysfunction and risk of AKI. This study evaluated FGF-23 as well as traditional markers of kidney disease, namely urine albumin-to-creatinine ratio (UACR) and creatinine-cystatin C estimated GFR (eGFRCrCyC), as risk factors for AKI in elderly individuals.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: Plasma FGF-23, UACR, and eGFRCrCyC were measured in 3241 community-dwelling elderly individuals in the Cardiovascular Health Study. Hospitalization for AKI was defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Associations of each biomarker with AKI were evaluated using Cox proportional hazards models adjusted for demographics, cardiovascular risk factors, and biomarkers of kidney function.

RESULTS: The mean participant age was 78 years; 60\% of participants were women and 16\% were African American. The median (interquartile range) values of biomarkers were as follows: FGF-23, 70 RU/ml (53, 99); UACR, 8.88 mg/g (4.71, 20.47); and eGFRCrCyC, 71 ml/min per 1.73 m(2) (59, 83). Hospitalized AKI occurred in 119 participants over 10.0 years of median follow-up. In fully adjusted analyses, compared with the lowest quartiles, the highest quartiles of FGF-23 (>=100 RU/ml) and UACR (>=20.9 mg/g) were associated with AKI (FGF-23: hazard ratio [HR], 1.99; 95\% confidence interval [95\% CI], 1.04 to 3.80; and UACR: HR, 3.35; 95\% CI, 1.83 to 6.13). Compared with the highest quartile, the lowest quartile of eGFRCrCyC (<57 ml/min per 1.73 m(2)) was associated with AKI with an HR of 2.15 (95\% CI, 1.21 to 3.82).

CONCLUSIONS: FGF-23 adjusted for albuminuria, cardiovascular disease risk factors, and baseline eGFR is independently associated with a higher risk of AKI hospitalizations in community-dwelling elderly individuals. Further studies to understand the nature of this association are warranted.

}, keywords = {Acute Kidney Injury, Age Factors, Aged, Aged, 80 and over, Albuminuria, Biomarkers, Creatinine, Cystatin C, Female, Fibroblast Growth Factors, Glomerular Filtration Rate, Hospitalization, Humans, Independent Living, Kidney, Longitudinal Studies, Male, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Factors, Time Factors}, issn = {1555-905X}, doi = {10.2215/CJN.05830513}, author = {Brown, Jeremiah R and Katz, Ronit and Ix, Joachim H and de Boer, Ian H and Siscovick, David S and Grams, Morgan E and Shlipak, Michael and Sarnak, Mark J} } @article {6662, title = {Fibroblast growth factor 23 and sudden versus non-sudden cardiac death: the Cardiovascular Health Study.}, journal = {Am J Kidney Dis}, volume = {66}, year = {2015}, month = {2015 Jul}, pages = {40-6}, abstract = {

BACKGROUND: Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with greater risk of cardiovascular events and mortality, especially among people with chronic kidney disease (CKD). Because individuals with CKD are at an increased risk of sudden cardiac death (SCD), we sought to understand whether FGF-23 level is a stronger risk factor for SCD versus non-SCD.

STUDY DESIGN: Cohort study.

SETTING \& PARTICIPANTS: 3,244 participants 65 years or older in the community-based Cardiovascular Health Study.

PREDICTOR: Plasma FGF-23 concentrations.

OUTCOMES: We assessed SCD and non-SCD in these analyses. SCD was adjudicated rigorously and was defined as a sudden pulseless condition of cardiac origin in a previously stable person occurring out of hospital or in the emergency department.

MEASUREMENTS: We estimated associations of baseline FGF-23 concentrations with SCD and non-SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, comorbid conditions, and kidney function. We also tested whether associations differed by CKD status.

RESULTS: During a median follow-up of 8.1 years, there were 118 adjudicated SCD and 570 non-SCD events. After multivariable adjustment for demographics, cardiovascular risk factors, comorbid conditions, and parameters of kidney function, higher FGF-23 concentrations were an independent risk factor for non-SCD (HR [per doubling], 1.17; 95\% CI, 1.06-1.30). However, elevated FGF-23 concentrations were not associated independently with SCD (HR [per doubling], 1.07; 95\% CI, 0.85-1.35). In stratified analysis by CKD status (36.5\% of cohort), doubling of FGF-23 concentrations was associated independently with non-SCD (adjusted HR, 1.26; 95\% CI, 1.10-1.45). A similar magnitude of association was observed between FGF-23 level and SCD in the CKD subgroup; however, it was not significant (HR, 1.20; 95\% CI, 0.89-1.62).

LIMITATIONS: Limited power to detect moderate-sized effects between FGF-23 level and SCD in both the primary and stratified analyses.

CONCLUSIONS: In this population-based study, FGF-23 level elevations were associated independently with non-SCD. Among individuals with CKD, the associations between FGF-23 level and SCD and non-SCD were similar.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Comorbidity, Death, Sudden, Cardiac, Electrocardiography, Female, Fibroblast Growth Factors, Follow-Up Studies, Heart Arrest, Heart Diseases, Humans, Kaplan-Meier Estimate, Male, Prospective Studies, Renal Insufficiency, Chronic, Risk Factors, Sympathetic Nervous System, United States}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2014.10.025}, author = {Deo, Rajat and Katz, Ronit and de Boer, Ian H and Sotoodehnia, Nona and Kestenbaum, Bryan and Mukamal, Kenneth J and Chonchol, Michel and Sarnak, Mark J and Siscovick, David and Shlipak, Michael G and Ix, Joachim H} }