**4. Fibroblast growth factor 23 and vascular calcification**

**3. Dysregulation of calcium and phosphate metabolism**

prescription is the most important risk factor in vascular calcification.

patients [25].

6 Updates in Hemodialysis

followed by SHPT [30].

Traditional risk factors, such as aging, hypertension, diabetes, and hyperlipidemia, and various nontraditional factors, including low serum calcium levels, high serum phosphate levels, high-dose prescription of CaCO3, chronic inflammation, and malnutrition, have been observed in ESRD patients [22]. Patients with advanced CKD demonstrate hyperphosphate‐ mia followed by reduced renal phosphate excretion. Vascular calcification is obviously related to impaired serum calcium and phosphate concentrations [16, 21, 23]. Elevated serum phos‐ phate concentration is found to be recognized as an arterial injury factor [24], and when phosphate control had been poorest, vascular calcification had rapidly progressed in CKD

There are two different mechanisms of vascular calcification that are proposed to verify the relationship between abnormal calcium and phosphate metabolism and vascular calcification. Previous studies have shown that calcium is a key element in the initiation of vascular calcification by promoting calcium deposition in VSMCs under normal phosphate metabolism [26], and when the phosphate levels are increased, this calcium deposition has been enhanced additionally [27]. Hyperphosphatemia may directly cause vascular injury, and it indirectly promotes osteoblastic differentiation via a type III sodium-dependent phosphate cotransporter (PiT-1). A previous report [28] demonstrated that an increased intracellular phosphate concentration may directly enhance VSMCs to differentiate to calcifying cells by activating genes. In addition, El-Abbadi et al. [29] has shown an experimental model of CKD-related vascular calcification in which severe arterial calcification progresses only after the mice are treated with a high-phosphate diet, indicating that hyperphosphatemia is a powerful stimu‐ lator of arterial calcification. These results suggest that high-dose phosphate and calcium

It is recognized that secondary hyperparathyroidism (SHPT) is common in ESRD patients and appears even in the early stage of CKD. Mineral metabolism disorders, such as hyperphos‐ phatemia, is associated with the progression of CKD stage, leading to the occurrence of SHPT, which is detected by elevated serum parathyroid hormone (PTH) concentrations and para‐ thyroid gland hyperplasia [30]. Increased PTH concentration is critical for the proliferation and activation of osteoclasts and important for the enhanced bone resorption in these patients. A remarkable reduction in serum 1,25-dihydroxyvitamin D [1,25(OH)2D] concentration is detected in the early stage of CKD [31], and the decrease in 1,25(OH)2D level is associated with renal and nonrenal mediators, such as decreased sun light exposure, reduced synthesis of the 25(OH) D precursor, and decreased dietary injection [32]. Reduced vitamin D production occurs in parallel with CKD progression and stimulates parathyroid gland enlargement,

Decreased 25(OH)D concentrations influenced survival independently of vascular calcinosis and increased arterial stiffness, indicating that 25(OH)D may affect mortality of CKD patients through additional mechanisms that require to be expected [33]. Active vitamin D promotes intestinal uptake of calcium and phosphate and stimulates osteoblastic transformation of VSMCs. Furthermore, 1,25(OH)2D has been known to play a role as a negative modulator of

Fibroblast growth factor 23 (FGF-23) is a new regulator produced by osteoblasts, which is associated with the regulation of phosphate and vitamin D metabolism [37]. FGF-23 has been shown to reduce the synthesis and promote the degradation of 1,25(OH)2D. Actually, recombinant FGF-23 suppresses renal 25-hydroxyvitamin D-1α-hydroxylase mRNA within 1 h in mice [38]. The enhanced degradation of 1,25(OH)2D by 24-hydroxylase may be related to this phenomenon. In addition, a phosphaturic effect of FGF-23 contributes to decreased phosphate uptake in the kidney. FGF-23 has been shown to down-regulate types IIa and IIc sodium-phosphate cotransporters on the apical area of proximal epithelial cells [38, 39].

Klotho has been reported as a 130-kDa β-glucuronidase that catalyzes the hydrolysis of steroid β-glucuronides [40]. The Klotho gene is mainly expressed in the kidneys, and its mutation induces many aging-associated diseases [41]. Since the phenotype of FGF-23-knockout (KO) mice is similar to those of Klotho-KO mice [42, 43], a common signaling pathway has been proposed, FGF-23 receptors (FGF-Rs). FGF-23 acts via FGF receptors (FGF-Rs) in a Klothodependent manner since a Klotho/FGF-R complex binds to FGF-23 with higher affinity than FGF-R or Klotho only [44]. FGF-23 has lower affinity for its receptors, and the combination with circulating Klotho is important to enhance the binding of FGF-23 to FGF-Rs [45]. Taken together, the activation of FGFRs needs not only circulating FGF-23 as a ligand but also Klotho as a specific activator those affinity attributes the selectivity on target organs.

Klotho is mainly present in the kidneys, whereas FGF-23 secretes from bone cells, and this bone–kidney interaction is essential for physiological and pathological mechanism. According to recent information, it is likely that this axis exerts a fundamental regulation of calcium metabolism with Klotho and to show a more specific effect on phosphate homeostasis via the presence of FGF-23. Both Klotho and FGF-23 affect synthesis of active vitamin D and PTH, indicating that FGF-23 may control PTH secretion in the parathyroid glands. In support of this mechanism, results obtained *in vitro* suggest that FGF-23 suppresses PTH mRNA transcription and protein secretion in a dose-dependent manner [46]. On the other hand, PTH promotes FGF-23 production by osteoblasts because increased FGF-23 concentrations in animals with primary HPT occur, which is decreased by parathyroidectomy [47].
