**7. Applicable therapy of vascular calcification**

Hyperphosphatemia is associated with SHPT and contributes to cardiovascular and allcause mortality. The phosphate binders are recently utilized to treat hyperphosphatemia, including sevelamer, lanthanum, and the calcium-based phosphate binders (CBPBs) such as CaCO3. Sevelamer is a calcium-free phosphate binder that does not increase serum calcium concentrations, enables better serum phosphate management than CBPBs, re‐ duces the extent of aortic calcification in ESRD patients, and improves serum lipid profile because it decreases low-density lipoprotein cholesterol (LDL-C) and induces the increase in high-density lipoprotein cholesterol (HDL-C) [72]. In a clinical study consisting of 200 HD patients, Chertow et al. [73] showed that sevelamer had significantly reduced the extent of coronary and aortic calcification compared with CBPBs after 1 year of therapy. These results were reevaluated by other investigators [74], who demonstrated that sevelamer significantly reduced the progression of vascular calcification when compared with CaCO3. One of the possible mechanism is a strong phosphate-binding ability of sevelamer in the intestine, without calcium overload. In the Renagel in New Dialysis study including HD patients with pretreatment CAC scores of 30 or higher, no significant difference was detected in the rate of CAC progression up to 18 months of follow-up between the sevelamer group and CBPB group [75]. *In vitro* experimental studies have demonstrated that acetylat‐ ed LDL-C induces calcium deposition, whereas HDL-C reduces it in cultured VSMCs [76]. In *in vivo* human studies, sevelamer has been shown to decrease LDL-C and to increase HDL-C concentrations. This improved lipid profile may be associated with the lowering grade of vascular calcification found after sevelamer therapy. These findings were con‐ firmed with the evidence that intensive LDL-C-lowering therapy with atorvastatin in the Calcium Acetate Renagel Evaluation-2 study demonstrated similar effects on the extent of CAC in HD patients treated with sevelamer and those treated with calcium acetate [77].

The calcium-sensing receptor (CaR) is a G protein-coupled receptor that binds calcium ions and makes it possible to respond to changes in the extracellular calcium ion levels [78]. CaR expression in the arterial wall has been found to be profoundly decreased in HD patients compared with normal subjects [79]. These results are compatible with those reported by Alam et al. [80], who showed lower expression CaR in the calcified human arteries compared with those without calcification. These findings indicate that CaR expression was closely associated with vascular calcification in the vessel wall. Ivanovski et al. [81] showed finding of direct suppression of phosphate-stimulated calcium deposi‐ tion in cultured human VSMC *in vitro* by a calcimimetic R-568, through local CaR activa‐ tion. Lopez et al. [82] examined the effect of the R-568 alone and in combination with calcitriol on the induction of vascular calcification in a uremic rat model with SHPT. The results of the experiment indicated that the R-568 decreased serum PTH concentrations without induction of vascular calcification, suppressed calcitriol-stimulated calcium deposition on vasculature, and reduced mortality rate related to supplementation of calcitriol. They concluded that R-568 suppresses increased serum PTH concentrations in uremic rats and inhibits calcitriol-stimulated calcium deposition in arterial tissues.

Bisphosphonates might play a possible role in the treatment of vascular calcification because these agents have been found to eliminate vascular calcification in experimental animal models. Tamura et al. [83] previously reported that etidronate suppressed calcitriolstimulated aortic calcium deposition in uremic rats. They showed that 2 mg/kg of etidro‐ nate was not effective but that 5–10 mg/kg of etidronate inhibited calcium deposition in the aorta. In another experimental study using cultured bovine VSMCs, pamidronate reduced arterial calcium deposition [84]. In clinical studies, etidronate has been found to suppress and even reverse the CAC progression in some of HD patients [8, 85], but the mechanism is unclear. Bisphosphonates suppress bone resorption, with decreased efflux of calcium and phosphate, limiting their deposition in the vascular tissues, or may affect the function of the sodium/phosphate cotransporter in VSMCs [86].

There are a few prospective randomized trials available in the literature with therapeutic interventions aimed at controlling vascular calcification and improving survival in patients with advanced CKD. Since there is an association between CKD-MBD, vascular calcifica‐ tion and mortality, mineral balance abnormalities became an obvious target for therapeu‐ tic interventions. Unfortunately, no additional data have been published to change the perspective in the KDIGO guidelines [69]. The EVOLVE trial in 3883 HD patients was conducted to test the hypothesis that treatment with cinacalcet would reduce the risks of death and nonfatal cardiovascular events [87]. However, no benefit was demonstrated from using the calcimimetic agent.
