2 steroid b-glucoronides. It was named after Klotho, one of the Moirae (the fates) in Greek mythology who spun the thread of life from her distaﬀ onto her spindle; indeed, Klotho- deﬁcient mice manifest a syndrome resembling acceler- ated human aging and extensive atherosclerosis. Because FGF-23/mice show similar phenotypes to Klotho/mice, a common signaling pathway has been postulated [13, 14]. Klotho gene expression was detected in cells of the renal tubule, parathyroid, and choroid plexus. Importantly, renal Klotho expression is largely conﬁned to the distal tubules, which is also the site for initial FGF-23 binding and signaling [15, 16]. However, renal phosphate reabsorption mainly occurs in the proximal tubules, and it is currently unknown how FGF-23 signaling in the distal tubule trans- lates into decreased phosphate reabsorption in the proximal tubules. 3. Physiological Functions of FGF-23 Renal phosphate excretion is physiologically regulated main- ly by proximal tubular cells, which express both Na/Pi Type II and Na/Pi IIc cotransporters at their apical membrane [17]. FGF-23 reduces the action of both cotransporters; in addition, it may inhibit gastrointestinal phosphate absorp- tion by reducing intestinal Na/Pi IIb cotransporter activity in a vitamin D-dependent manner [18]. The principal physiological stimuli for increased FGF-23 expression both in vitro and in vivo are 1,25(OH)2D3 and high dietary phosphate intake [19–22]. Persistent hyper- phosphataemia is an eﬀective trigger for FGF-23, while rapid changes in serum phosphate concentrations may not induce an acute increment in serum FGF-23 levels [23]. It is therefore possible that FGF-23 responds to the net phosphate balance rather than to the serum phosphate level, but experimental data supporting this hypothesis are scarce. 4. FGF-23, PTH, and Calcitriol FGF-23, PTH, and calcitriol may inﬂuence each other in opposite manner. FGF-R and Klotho are expressed in parathyroid glands; FGF-23 might decrease PTH mRNA transcription [24]. FGF-23 activity is not dependent on PTH, as the phosphaturic eﬀects of FGF-23 are maintained in animals after parathyroidectomy [25]. Conversely, PTH may stimulate FGF-23 secretion by osteoblast, as FGF-23 levels are increased in rodents with primary HPT, which may be reversed by parathyroidectomy [26]. In rodents, injection of recombinant FGF-23 reduces calcitriol levels within hours by decreasing renal expression of 1a-hydroxylase (CYP27B1) and increasing the expression of 24-hydroxylase (CYP24A1), which controls calcitriol degradation [25]. Conversely, cal- citriol itself stimulates FGF-23 generation by binding to a vitamin D response region in the FGF-23 gene promoter [27]. International Journal of Nephrology 5. FGF-23 in Subjects with Intact Renal Function The main physiological role of FGF-23 in healthy subjects is to regulate urinary phosphate excretion to maintain stable serum phosphate levels. However, no correlation between FGF-23 and serum phosphate levels has been found in individuals without overt renal disease [28, 29]. Possible explanation for this ﬁnding is that most studies which found no signiﬁcant change in FGF-23 levels were smaller, and phosphate loading was restricted to a maximum of 3 days [21]. 6. FGF-23 23 in Subjects with CKD In CKD, circulating FGF-23 levels gradually increase with declining renal function such that by the time patients reach end-stage renal disease, FGF23 levels can be up to 1000-fold above the normal range [30]. The increase in FGF-23 begins at a very early stage of CKD as a physiological compensation to stabilize serum phosphate levels as the number of intact nephrons declines [28, 30–32]. In contrast, it was hypothesized that increased FGF-23 levels in CKD result primarily from decreased renal clearance [31]. However, there is no increase in the accumulation of degraded FGF-23 in advanced CKD. It is also likely that FGF-23 levels depend on an increased secretion due to an end-organ resistance to the phosphaturic stimulus of FGF-23 because of a deﬁciency of the necessary Klotho cofactor [33, 34]. Other potential explanations for the early rise in FGF-23 could be the release of unidentiﬁed FGF-23 stimulatory factors or loss of a negative feedback factor(s) that normally suppress FGF-23, by the failing kidney. 7. FGF-23, Mortality, and Cardiovascular End Points Since alterations in mineral metabolism are associated with increased cardiovascular risk in CKD, it is plausible that FGF-23 is directly involved in it. Indeed, in patients starting hemodialysis, higher FGF-23 levels were strongly associated with increased risk of 1-year mortality both in crude- and multivariate-adjusted models, with the highest FGF-23 quar- tile reaching a nearly 6-fold higher risk than the lowest [35]. In addition, in this population, FGF-23 was stronger predic- tor of mortality than the serum phosphate level. Importantly, FGF23 did not associate to mortality in patients within the highest quartile of serum phosphate (>1.77 mmol/L), suggesting that the prognostic value of FGF23 is blunted in the presence of severe hyperphosphatemia. The role of FGF-23 on cardiovascular or renal end points but not on mortality has been evaluated in patients with CKD not on dialysis. In 227 diabetic patients with CKD stages 1–4, the progression of renal disease was assessed [32]. It was found that FGF-23 but not serum phosphate levels was signiﬁcant independent predictor of CKD progression, deﬁned as doubling of serum creatinine and/or terminal renal failure. In a cross-sectional study, a large cohort of