**2. Pathophysiology and bone-associated proteins**

**Fig. 2**

Fig. 1

4 Updates in Hemodialysis

**Intimal calcification**

**Matrix vesicles**

Differentiation of SMC to osteoblast-like cells

**collagen**

**Atherosclerosis**

**Stenosis, occlusion**

**Infarction, ischemia**

**Arterial calcification**

**Matrix Mineralization**

**Figure 1.** Relationship between calcium and phosphorus and vascular calcification.

**SMC phenotype modulation - Runx2**

**- osteocalcin Mineral**

**- alkaline phosphatase**

**Pit-1**

**P↑**

**Na P**

**Figure 2.** Schematic representation of the clinical effects of arterial intimal and medial calcification.

Recent therapeutic regimens that are performed to suppress vascular calcification are concen‐ trated on the control of metabolic markers of skeletal disorder, including phosphate, and

**Medial calcification**

**Ca/P loading of matrix vesicles**

**Elevated Phosphate Elevated Calcium**

**↑Ca / P** 

**Arteriosclerosis**

**Stiffening**

**↑Systolic and pulse pressures, early return of wave reflections**

**Altered coronary perfusion, left-ventricular hypertrophy** The pathophysiology of vascular disorder in HD patients is recently recognized as different from the pathophysiology of atherosclerotic alterations in healthy subjects [10]. Vascular calcification progresses in association with aging, and deposition of calcium in the media is > 30-times more in the thoracic aorta at 90 years old than those at 20 years old [11]. Age-associated medial calcinosis in arteries is also related to hypertension, diabetes, and hyperlipidemia [12], and it is specific for arteries and does not affect other soft tissues in normal subjects. Vascular calcification was previously considered as a passive finding, but it has recently been recognized as an active process [13–15].

Two patterns of vascular calcification have been reported. One appears in the intimal layer and the other occurs in the medial layer of the vessel wall which is known as in Monckeberg's calcification [16], and both types are related to increased mortality of HD patients [17]. Intimal calcification is found to be related to chronic inflammatory changes and the occurrence of plaques and occlusive lesions. This intimal type of calcification is a predictor of the advanced atherosclerosis and is found to be seen in the aorta and coronary arteries. Medial calcification is identified with diffuse calcium deposition and can occur independent of atherosclerosis, and it is frequently shown in conduit arteries, including the femoral and tibial arteries [13, 16].

There are well-known changes in the arterial wall, such as intimal thickening, calcification of elastic lamellae, an increased extracellular matrix, and deposition of collagen and a relatively small elastic fiber content, and these findings are associated with arterial remodeling in CKD patients [17]. Numerous bone-related proteins, including osteopontin, osteocalcin, and osteoprotegerin (OPG), and bone morphogenetic proteins (BMPs) are associated with the vascular remodeling, and they are found to be appeared in the calcified lesions and are known to be related to vascular calcification [18]. VSMCs are the main component of the arterial media, and they can transform to osteoblast-like cells in association with up-regulation of transcrip‐ tion factors, such as Runt-related transcription factor 2 (Runx2) and Msh homeobox 2 (Msx2), which are important factors for normal bone formation [19]. This phenotypic differentiation may be related to the deposition of calcium in the layer of VSMCs that is similar to bone development, indicating that this type of vascular calcification is ectopic ossification. In addition, uremic condition has been found to induce transformation of VSMCs into osteoblastlike cells and suppresses the transformation of macrophages into osteoclasts [20]. The arteries of HD patients demonstrate up-regulation of alkaline phosphatase activity and enhanced expression of Runx2, which is predictor of osteogenic differentiation of VSMCs [21].
