Plasma FGF23 and cardiovascular mortality in relation to kidney function among adults with established cardiovascular disease

Abstract

Fibroblast growth factor-23 (FGF23) has been linked to adverse cardiovascular phenotypes, yet its prognostic relevance among individuals with prevalent cardiovascular disease and the potential modifying role of kidney function remain unclear. We analyzed 9,119 UK Biobank participants with established cardiovascular disease (CVD) at baseline. The association between baseline plasma FGF23, measured on the original Olink normalized protein expression (NPX) scale, and CVD-specific mortality was examined using multivariable Cox models. Kidney function (eGFR, ACR) was prespecified for effect modification. Dose–response patterns were assessed using restricted cubic spline models, and the robustness of the findings was evaluated through sensitivity and competing-risk analyses. Over a median follow-up of 13.66 years, 595 CVD-specific deaths occurred. After simultaneous adjustment for continuous eGFR, log-transformed ACR, and other prespecified covariates, each 1-unit increase in FGF23 NPX was associated with a higher cause-specific hazard of CVD-specific mortality (HR, 1.375; 95% CI, 1.268–1.492). The corresponding HRs were 1.524 (95% CI, 1.390–1.671) among participants with eGFR ≥ 60 mL/min/1.73 m 2 and 1.181 (95% CI, 1.032–1.351) among those with eGFR < 60 mL/min/1.73 m 2 , with a significant FGF23-by-eGFR interaction in the log-linear model (interaction HR, 0.775; P = 0.002). The interaction with ACR was not statistically significant (interaction HR, 0.914; P = 0.206). Dose–response associations were significant and nonlinear across the eGFR and ACR strata. Among individuals with prevalent CVD, higher baseline FGF23 was associated with a higher long-term cause-specific hazard of CVD mortality. In the log-linear model, the association per 1-unit increase in FGF23 NPX differed by eGFR category, with a lower HR among participants with eGFR < 60 mL/min/1.73 m 2 than among those with eGFR ≥ 60 mL/min/1.73 m 2 , whereas the interaction with ACR was not statistically significant. These findings highlight kidney function as an important context for interpreting the prognostic association of FGF23.