Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2-4

Abstract

Background and objectives: CKD-mineral and bone disorders (CKD-MBD) measures contribute to cardiovascular morbidity in patients with CKD. Among these, fibroblast growth factor (FGF)-23 and its coreceptor Klotho may exert direct effects on vascular and myocardial tissues. Klotho exists in a membrane-bound and a soluble form (sKlotho). Recent experimental evidence suggests sKlotho has vasculoprotective functions.

Design, settings, participants, & measurements: Traditional and novel CKD-MBD variables were measured among 444 patients with CKD stages 2-4 recruited between September 2008 and November 2012 into the ongoing CARE FOR HOMe study. Across tertiles of baseline sKlotho and FGF-23, the incidence of two distinct combined end points was analyzed: (1) the first occurrence of an atherosclerotic event or death from any cause and (2) the time until hospital admission for decompensated heart failure or death from any cause.

Results: Patients were followed for 2.6 (interquartile range, 1.4-3.6) years. sKlotho tertiles predicted neither atherosclerotic events/death (fully adjusted Cox regression analysis: hazard ratio [HR] for third versus first sKlotho tertile, 0.75 [95% confidence interval (95% CI), 0.43-1.30]; P=0.30) nor the occurrence of decompensated heart failure/death (HR for third versus first sKlotho tertile, 0.81 [95% CI, 0.39-1.66]; P=0.56). In contrast, patients in the highest FGF-23 tertile had higher risk for both end points in univariate analysis. Adjustment for kidney function attenuated the association between FGF-23 and atherosclerotic events/death (HR for third versus first FGF-23 tertile, 1.23 [95% CI, 0.58-2.61]; P=0.59), whereas the association between FGF-23 and decompensated heart failure/death remained significant after adjustment for confounders (HR for third versus first FGF-23 tertile, 4.51 [95% CI, 1.33-15.21]; P=0.02).

Conclusions: In this prospective observational study of limited sample size, sKlotho was not significantly related to cardiovascular outcomes. FGF-23 was significantly associated with future decompensated heart failure but not incident atherosclerotic events.

Keywords: arteriosclerosis; calcium; chronic renal disease; fibroblast.

Figure 1.

Secreted Klotho (sKlotho) is not predictive for (A) atheroslcerotic events/death and (B) decompensated heart failure/death in univariate analysis. Patients were stratified into tertiles by their plasma sKlotho levels (Kaplan–Meier analysis with log-rank test).

Figure 2.

Fibroblast growth factor (FGF)-23 is predictive for (A) atherosclerotic events/death and (B) decompensated heart failure/death in univariate analysis. Patients were stratified into tertiles by their plasma FGF-23 levels (Kaplan–Meier analysis with log-rank test).

Figure 3.

FGF-23 is an independent predictor for decompensated heart failure/death in multivariate analysis. Patients were stratified into tertiles by their plasma FGF-23 levels (multivariate Cox regression analysis). HR, hazard ratio.