Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population☆
Introduction
Fibroblast growth factor-23 (FGF23) is a circulating, bone-derived factor that plays a critical role in regulation of bone and mineral metabolism [1], [2], [3]. A major target organ for FGF23 is the kidney as it inhibits the reabsorption of inorganic phosphate (Pi) in the proximal tubules through down-regulation and internalization of the sodium/Pi co-transporters type IIa and c (Npt2a, Npt2c) [4], [5]. FGF23 also prevents calcitriol synthesis through direct regulation of key enzymes regulating vitamin D metabolism [2], [6].
FGF23 is aberrantly expressed in chronic kidney disease (CKD) stage 4–5, where serum levels can reach more than a 1000-fold increase above the normal range [7]. Elevated FGF23 levels in CKD are mainly driven by persistent hyperphosphataemia due to Pi retention, although FGF23 also serves as a negative regulator of PTH synthesis and secretion [8], [9]. The systemic effects of supra-physiological FGF23 concentrations remain elusive, however, they are inevitably linked to unfavourable outcomes, such as faster progression of renal failure in moderate CKD [10] and increased mortality in incident hemodialysis patients [11].
Cardiovascular morbidity and mortality are highly prevalent in CKD [12]. Major cardiovascular risk factors are left ventricular hypertrophy (LVH) [13] and a high left ventricular mass index (LVMI) [14], which predict increased mortality both in CKD [15], [16], [17] and in the general population [13]. Consequently, LVH is one of the main targets for cardiovascular intervention in CKD [18].
Given the high prevalence of cardiovascular disease in CKD, paralleled by elevated FGF23 levels linked to poor outcomes, we hypothesized that FGF23 may be associated with established cardiovascular risk factors. In support, we recently showed a graded relation between FGF23, endothelium dysfunction and arterial stiffness in a community-based setting [19]. In addition, we have also shown an association between FGF23 and the severity of atherosclerosis [20]. Herein, we evaluated the relation between serum FGF23, LVMI, LVH and left ventricular (LV) geometry in a large, community-based, cohort of men and women aged 70 with specific subgroup analysis in participants with an age-adjusted diminished renal function.
Section snippets
Study sample
Men and women living in the community of Uppsala, Sweden, were chosen from the community register and were in a randomized order invited by letter within 2 months after their 70th birthday to the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) [21]. Out of the 2025 subjects invited, 1016 subjects were investigated [21]. An analysis of non-participants showed the present sample to be representative of the total population regarding cardiovascular disorders and drug intake
Results
Basic characteristics, cardiovascular risk factors and serum biochemistries for the total cohort (n = 795) and subjects with eGFR < 60 mL/min/1.73 m2 are presented in Table 1.
Discussion
Measurement of circulating FGF23 in CKD has been suggested as a potentially valuable tool for prediction of secondary hyperparathyroidism [28], CKD progression rate [10], and over-all mortality risk in incident hemodialysis patients [11]. Elevated levels of FGF23 in CKD, paralleled by the devastating cardiovascular risk, makes it tempting to infer a possible role of FGF23 in cardiovascular pathology.
Herein, we for the first time demonstrate that FGF23 is positively associated with LVMI and
Conflict of interest
No competing interests.
Acknowledgement
We would like to thank Anna-Lena Johansson for technical assistance.
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This work was supported by the Swedish Research Council, the NovoNordisk Foundation, the Swedish Kidney Foundation and the Swedish Society of Medicine. The authors have nothing to declare. The funding sources did not play any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.