Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study)

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.

Figure 1. Relationship of Estimated Glomerular Filtration Rate (1A) and Urine Albumin to Creatinine Ratio (1B) with Fibroblast Growth Factor-23 in Community-Living Individuals

Cubic spline function demonstrating the adjusted cross-sectional association of (A) eGFR estimated by cystatin C and (B) ACR with plasma FGF-23 levels. Red lines represent the adjusted point estimates, and blue lines represent the 95% confidence intervals. The y-axis demonstrates the change in log FGF23. The spline functions for eGFR (Figure 1A) was adjusted for age, sex, race, and urine ACR. Spline function for ACR (Figure 1B) was adjusted for age, sex, race, and eGFR., The extreme 2.5% of the distribution of eGFR and ACR were excluded to avoid improbable extrapolations based on extremes of the data.

Figure 2. Associations of Fibroblast Growth Factor-23 Quartiles and Risk of All-Cause Mortality, Incident Heart Failure, and Incident CVD Events: The Cardiovascular Health Study

Annual event rates of (A) all-cause mortality, (B) incident heart failure, and (C) incident cardiovascular disease events by quartiles of FGF23, stratified by chronic kidney disease status. Patients with prevalent heart failure and cardiovascular disease at the baseline examination were excluded from figures 2B and 2C respectively.