SAGE-Hindawi Access to Research International Journal of Nephrology Volume 2011, Article ID 364890, 5 pages doi:10.4061/2011/364890 Review Article Clinical Signiﬁcance of FGF-23 in Patients with CKD Domenico Russo and Yuri Battaglia Department of Nephrology, School of Medicine, University Federico II, Via Pansini 5, 80131 Napoli, Italy Correspondence should be addressed to Domenico Russo, domenicorusso51@hotmail.com Received 22 December 2010; Accepted 24 February 2011 Academic Editor: Angela Wang Copyright © 2011 D. Russo and Y. Battaglia. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. FGF23 is a bone-derived hormone that plays an important role in the regulation of phosphate and 1,25-dihydroxy vitamin D metabolism. FGF23 principally acts in the kidney to induce urinary phosphate excretion and suppress 1,25-dihydroxyvitamin D synthesis in the presence of FGF receptor 1 (FGFR1) and its coreceptor Klotho. In patients with chronic kidney disease (CKD), circulating FGF23 levels are progressively increased to compensate for persistent phosphate retention, but this results in reduced renal production of 1,25-dihydroxyvitamin D and leads to hypersecretion of parathyroid hormone. Furthermore, FGF23 is associated with vascular dysfunction, atherosclerosis, and left ventricular hypertrophy. This paper summarizes the role of FGF23 in the pathogenesis of mineral, bone, and cadiovascular disorders in CKD. 1. Introduction Patients with chronic kidney disease (CKD) are at increased risk for cardiovascular events compared with individuals with normal kidney function [1]. In addition to tradi- tional cardiovascular risk factors, disturbances in calcium- phosphate metabolism are regarded as strong contributing factors of higher cardiovascular mortality in CKD patients [2, 3]. Indeed, elevated serum phosphate, low calcitriol, and high PTH levels represent the classical triad that leads to secondary hyperparathyroidism, each factor being independently associated with cardiovascular events and mortality in patients with CKD [4, 5]. Recently, the phosphaturic hormone, ﬁbroblast growth factor (FGF-23), is overpoweringly entered into the tradi- tional pathophysiological scheme of secondary hyperpara- thyroidism. 2. Structure of FGF-23 Seven known subfamilies of human FGFs have been deﬁned [6, 7]. The FGF-19 subfamily is composed of three pro- teins—FGF-19, FGF-21, and FGF-23—which exert diverse physiological functions. FGF-23 is a central regulator of phosphate homeostasis and calcitriol blood levels; FGF-19 inhibits the expression of enzyme cholesterol 7-a- hydroxylase (CYP7A1), which is the ﬁrst and rate-limiting step in bile acid synthesis [8]; FGF-21 stimulates insulin- independent glucose uptake in adipocytes and lowers triglyc- erides [9]. Interestingly, FGF-19, FGF-21, and FGF-23 con- tain a disulﬁde bond that is absent in most other subfamilies. This may explain why FGF-23 can be distributed in the bloodstream to mediate its functions. FGF-23 is a 251-amino acid protein (MW 26 kDa) syn- thesized and secreted by bone cells, mainly osteoblast [10]. It is composed of an amino-terminal signal peptide (residues 1–24), followed by an “FGF-like sequence” (residues 25–180) and a carboxyl-terminal extended sequence (residues 181– 251) that is unique compared with other members of the FGF family [7]. The half-life of intact FGF-23 in the circulation of healthy individuals has been estimated to be 58 min [11]. FGF-23 exerts its biological eﬀects through activation of FGF receptors (FGF-Rs); this activation is Klotho dependent as a Klotho/FGF-R complex binds to FGF-23 with higher aﬃnity than does FGF-R or Klotho alone [12]. Klotho is a 130- kDa transmembrane b-glucuronidase capable of hydrolyzing