Circulating fibroblast growth factor 21, renal function, and aortic hemodynamics in middle‐aged and older adults: a mediation analysis

Abstract

Introduction A decline in renal function is associated with aortic stiffening and hypertension. However, the pathophysiological mechanisms behind the relation between renal dysfunction and altered aortic hemodynamics have not been fully elucidated. Fibroblast growth factor 21 (FGF21), which is an endocrine substance that is mainly secreted from the liver, has been reported to alter aortic hemodynamics via upregulation of sympathetic nerve activity. On the other hand, it has been demonstrated that circulating FGF21 levels were increased with decline of renal function. These findings have led us to hypothesize that elevated circulating levels of FGF21 may mediate the link between renal dysfunction, advanced aortic stiffness, and elevated blood pressure. Therefore, this study aimed to determine whether circulating FGF21 levels may mediate altered aortic hemodynamics in middle-aged and older adults with declined renal function. Methods Two-hundred ninety-nine middle-aged and older adults (age range: 46-83 years, percentage of men: 36%) were included in this study. To assess renal function, the estimated glomerular filtration rate (eGFR) was measured. The range of eGFR was 18 to 145 mL/min/1.73m2. Aortic blood pressure was measured by applanation tonometry. Aortic stiffness was measured by carotid-femoral pulse wave velocity (cfPWV) using a standard procedure. Serum FGF21 levels were measured by ELISA. In the mediation analysis, aortic blood pressure and stiffness (cfPWV) were entered as outcomes respectively. The predictor and mediator were set for eGFR and log-transformed serum FGF21 levels respectively. Results Serum FGF21 levels were significantly correlated with aortic pulse pressure (r = 0.200) and cfPWV (r = 0.326). Moreover, eGFR was negatively correlated with aortic pulse pressure (r = −0.188) and cfPWV (r = −0.390). In multivariable regression models adjusting for the potential covariates including age, sex, body mass index, heart rate, current smoking status, anti-hypertensive, lipid lowering, and hypoglycemic medication use, serum FGF21 level was independently associated with aortic pulse pressure (β = 0.132) and cfPWV (β = 0.173). The mediation analysis demonstrated that serum FGF21 significantly mediates the relations of eGFR with aortic pulse pressure (indirect effect [95% CI]: −0.018 [−0.036, −0.003]) and cfPWV (−0.592 [−1.122, −0.184]). The percentages of these indirect effects were 33% and 34% of the total effect respectively. Conclusion The present study showed that circulating FGF21 level is independently associated with aortic hemodynamic parameters in middle-aged and older adults. Also, mediation analysis demonstrated that circulating FGF21 level mediated the association of renal function with aortic pulse pressure and stiffness. These findings suggest that elevated blood pressure and advanced aortic stiffness with decreased renal function may be partly mediated by the elevated circulating level of FGF21 in middle-aged and older adults.