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

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 patients [25].

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 prescription is the most important risk factor in vascular calcification.

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, followed by SHPT [30].

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 the renin–angiotensin axis, which acts an important key element in the cardiovascular system by controlling extracellular volume and electrolyte metabolism [34]. Even though high-dose of 1,25(OH)2D promotes arterial calcinosis [35], normal doses have been reported to inhibit arterial calcinosis in experimental models of CKD [36].
