International Journal of Nephrology men and women in CKD stage 2 with a mean eGFR of 73 mL/min/1.73 m2 was evaluated. In this cohort, that represented a valuable model of healthy individuals and early CKD, it was observed that higher FGF-23 was linked to several dynamic measurements of vascular function, includ- ing arterial stiﬀness measured by pulse wave velocity and endothelial dysfunction measured by an invasive forearm technique [36] in both crude- and multivariate-adjusted models. A subgroup of this population underwent a novel technique named whole-body magnetic resonance imaging angiography, which provides information about the degree of arterial stenosis as a surrogate marker of atherosclerosis in all major vascular territories. Higher FGF-23 level was asso- ciated with higher atherosclerosis score [37]. It is important to underline that FGF-23 in some studies has been linked to peripheral vascular calciﬁcation and/or coronary artery calciﬁcation score, whereas other reports have failed to show such an association [29, 38–41]. On this regard, it has been speculated that FGF-23 could function as a local inhibitor of vascular calciﬁcation; FGF-23 inhibits calciﬁcation in vascular smooth muscle cells in vitro; this inhibitory eﬀect is strengthened in an inﬂamed setting, which is often present in CKD patients [42]. Given the osteogenic transformation of vascular smooth muscle cells that occurs in atherosclerotic plaques, it is possible that FGF-23 may be locally expressed in the cardiovascular system. But the presence of FGF-23 in the heart or aorta has not been demonstrated yet [43]. It is currently thought that, at least in early CKD, FGF-23 indi- rectly contributes to decreased vascular calciﬁcation through maintaining a normal serum phosphate level. Finally, the relation between FGF-23 and left ventricular hypertrophy has been evaluated, that is another strong cardiovascular risk factor in CKD. This issue is clinically relevant because other members of the FGF family have been implicated in the pathogenesis of myocardial hypertrophy. Serum FGF- 23 was positively associated with left ventricular mass index and increased risk of having left ventricular hypertrophy. In particular, these associations were found in the highest FGF-23 tertile (>48 pg/mL) and were strengthened when restricted to subjects with eGFR <60 mL/min/1.73 m2 [35]. It is worth noticing that the associations between FGF- 23, vascular dysfunction, atherosclerosis, and left ventricular hypertrophy were all progressively strengthened in patients with a lower eGFR despite normal phosphate levels. This ﬁnding supports the hypothesis that FGF-23 may reveal information about phosphate-related toxicity that cannot be obtained by measurements of serum phosphate. 8. Open Questions The mechanism by which FGF-23 increases cardiovascular events and mortality is still unclear. Thus, it is debated whether FGF-23 is merely a marker of disturbed calcium- phosphate metabolism, or it exerts its undesirable eﬀects by lowering vitamin D levels. Indeed, the correlation of FGF- 23 levels with serum phosphate in CKD patients [31, 32, 44, 45] and the association of hyperphosphatemia with adverse outcome in these patients [4, 5, 46–52] may suggest that 3 negative eﬀects of FGF-23 on survival are the mirror of the negative eﬀects of serum phosphorus. Alternatively, FGF- 23 may inﬂuence outcomes by inducing hypovitaminosis D suppressing 1a-hydroxylase with subsequent reduction in calcitriol secretion. Vitamin D deﬁciency is a nontradi- tional cardiovascular risk factor in CKD [53–55]. However, available data seem to exclude an ancillary role for FGF- 23 as mirror of serum phosphorus because adverse eﬀects associated with high FGF-23 levels remained statistically signiﬁcant after adjustment for phosphate, calcium, and PTH levels [32]. On the same way, adverse eﬀects associated with high FGF-23 levels remained statistically signiﬁcant after adjustment for vitamin D levels [35, 36]. In addition, FGF- 23 has recently been shown to antagonize some eﬀects of vitamin D in vitro; in a cell culture model, vitamin D induced cell apoptosis, whereas FGF-23 and Klotho induced cell proliferation [56]. Therefore, some hypotheses have been proposed. It has been hypothesized that FGF-23 at very high serum concentrations (as observed in CKD patients) may exert certain nonspeciﬁc and presumably adverse eﬀects through low-aﬃnity, Klotho-independent binding to FGF-R, for example, on endothelial cells [57]. 9. Conclusion FGF-23 is a regulator of calcium-phosphate metabolism. In clinical trials, elevated FGF-23 levels were independently associated with faster progression of CKD, therapy-resistant secondary hyperparathyroidism, left ventricular hypertro- phy, and increased cardiovascular mortality in dialysis patients. However, FGF-23 is not just a marker of the derangements of calcium-phosphate metabolism in CKD, but rather a relevant factor responsible for the inception of secondary hyperparathyroidism and for cardiovascular morbidity and mortality. Thus, FGF-23 could represent a promising therapeutic target that might improve the fatal prognosis of patients with CKD. Disclosure The authors declare that the content of this paper has not been published elsewhere and is not currently under con- sideration by another journal published by SAGE-Hindawi or any other publisher. The paper’s publication has been approved by all the other coauthors. References [1] R. N. Foley, P. S. Parfrey, and M. J. 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